Rodney Scott

Investigation of the expression of genes affecting cytomatrix active zone function in the amygdala in schizophrenia: Effects of antipsychotic drugs

Publisher: Elsevier BV

Date: 2009

DOI: 10.1016/J.JPSYCHIRES.2008.04.001

Abstract: The cytomatrix active zone (CAZ) is a specialized cellular structure regulating release of vesicles. We reported previously increased expression of three CAZ genes, piccolo, RIMS2 and RIMS3 in the amygdala in schizophrenia. This study determined the levels of gene and protein expression for components of the active zone including two additional CAZ genes in the amygdala from subjects with schizophrenia and non-psychiatric controls, as well as the effects of antipsychotic drugs. Whilst relative real-time PCR analysis did not identify significant change in the expression of six additional active zone genes, Western blot analysis showed increased piccolo and RIMS2 protein expression in the amygdala in schizophrenia. In vitro analysis suggests antipsychotic drug treatment was unlikely to have caused the changes in RIMS2, RIMS3 and piccolo expression observed in the amygdala in schizophrenia. Therefore, this study provides further evidence suggesting that piccolo, RIMS2, RIMS3, but not the entire components of the active zone are involved in the neurobiology of schizophrenia.

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Publisher: Springer Science and Business Media LLC

Date: 02-2016

DOI: 10.1038/NN.4228

The 3′ untranslated region C > T polymorphism of prohibitin is a breast cancer risk modifier in Polish women carrying a BRCA1 mutation

Publisher: Springer Science and Business Media LLC

Date: 27-09-2007

DOI: 10.1007/S10549-006-9389-3

Abstract: The variable penetrance of breast cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. The C to T transition in the 3' untranslated region of the prohibitin (PHB) gene alters mRNA function and has been shown to be associated with an increased breast cancer risk among young North-American women who have one first-degree relative with breast cancer. To investigate whether the PHB 3'UTR polymorphism acts as a modifier of hereditary breast cancer risk we performed a case-control study among female BRCA1 mutation carriers, which included 258 cases and 258 controls who were unaffected by ovarian cancer, in situ breast carcinoma or any other type of cancer. Controls were matched to cases by year of birth and BRCA1 mutation (5382insC, 300 T > G, 4153delA). Genotyping analysis was performed using RFLP-PCR. Odds ratios (OR) were calculated using conditional and penalised univariable and multivariable logistic regression. Multivariable penalised logistic regression revealed CT (OR(adj), 2.03 95% CI, 1.17-3.59) and combined CT + TT (OR(adj), 2.12 95% CI, 1.23-3.70) genotypes as significant modifiers of breast cancer risk. Breast cancer risk did not differ between carriers of the 300 T > G and 5382insC mutation. Our results suggest that the PHB 3'UTR T allele increases the risk of breast cancer in patients who are already at increased risk of disease.

Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis

Publisher: Public Library of Science (PLoS)

Date: 11-01-2013

DOI: 10.1371/JOURNAL.PONE.0053830

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Publisher: Springer Science and Business Media LLC

Date: 12-05-2021

DOI: 10.1038/S41523-021-00255-3

Abstract: Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

Molecular Epidemiology of HIV Transmission in a Dental Practice

Publisher: American Association for the Advancement of Science (AAAS)

Date: 22-05-1992

DOI: 10.1126/SCIENCE.256.5060.1165

Abstract: Human immunodeficiency virus type 1 (HIV-1) transmission from infected patients to health-care workers has been well documented, but transmission from an infected health-care worker to a patient has not been reported. After identification of an acquired immunodeficiency syndrome (AIDS) patient who had no known risk factors for HIV infection but who had undergone an invasive procedure performed by a dentist with AIDS, six other patients of this dentist were found to be HIV-infected. Molecular biologic studies were conducted to complement the epidemiologic investigation. Portions of the HIV proviral envelope gene from each of the seven patients, the dentist, and 35 HIV-infected persons from the local geographic area were lified by polymerase chain reaction and sequenced. Three separate comparative genetic analyses--genetic distance measurements, phylogenetic tree analysis, and amino acid signature pattern analysis--showed that the viruses from the dentist and five dental patients were closely related. These data, together with the epidemiologic investigation, indicated that these patients became infected with HIV while receiving care from a dentist with AIDS.

Gene expression profiles in whole blood and associations with metabolic dysregulation in obesity

Publisher: Elsevier BV

Date: 03-2018

DOI: 10.1016/J.ORCP.2017.07.001

Abstract: Gene expression data provides one tool to gain further insight into the complex biological interactions linking obesity and metabolic disease. This study examined associations between blood gene expression profiles and metabolic disease in obesity. Whole blood gene expression profiles, performed using the Illumina HT-12v4 Human Expression Beadchip, were compared between (i) in iduals with obesity (O) or lean (L) in iduals (n=21 each), (ii) in iduals with (M) or without (H) Metabolic Syndrome (n=11 each) matched on age and gender. Enrichment of differentially expressed genes (DEG) into biological pathways was assessed using Ingenuity Pathway Analysis. Association between sets of genes from biological pathways considered functionally relevant and Metabolic Syndrome were further assessed using an area under the curve (AUC) and cross-validated classification rate (CR). For OvL, only 50 genes were significantly differentially expressed based on the selected differential expression threshold (1.2-fold, p<0.05). For MvH, 582 genes were significantly differentially expressed (1.2-fold, p<0.05) and pathway analysis revealed enrichment of DEG into a erse set of pathways including immune/inflammatory control, insulin signalling and mitochondrial function pathways. Gene sets from the mTOR signalling pathways demonstrated the strongest association with Metabolic Syndrome (p=8.1×10 These results support the use of expression profiling in whole blood in the absence of more specific tissue types for investigations of metabolic disease. Using a pathway analysis approach it was possible to identify an enrichment of DEG into biological pathways that could be targeted for in vitro follow-up.

Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples

Publisher: Elsevier BV

Date: 2011

DOI: 10.1016/J.JACI.2010.10.024

Abstract: Previous studies have identified clinical or inflammatory phenotypes of asthma on the basis of clinical and demographic parameters or sputum cell counts however, few studies have defined transcriptional phenotypes of asthma. To investigate asthma phenotypes at a transcriptional level by using gene expression profiling of induced sputum. Induced sputum s les were collected from 59 people with asthma with a mean age of 58 years and an FEV(1)% predicted of 76%, and 69% were taking inhaled corticosteroids. Thirteen healthy controls without asthma were also assessed. Inflammatory cell counts were performed, and RNA was extracted from selected sputum. Transcriptional profiles were generated (Illumina Humanref-8 V2) and analyzed by using GeneSpring GX11. Unsupervised hierarchical clustering of gene expression profiles in asthma revealed 3 distinct groups. The first transcriptional phenotype (n = 21) had lower FEV(1)% predicted and higher asthma control questionnaire scores, exhaled nitric oxide, and sputum eosinophils. The second transcriptional phenotype (n = 14) had lower FEV(1)% predicted and forced vital capacity % predicted and higher sputum neutrophils compared with a third transcriptional phenotype (n = 24) that had higher sputum macrophages and resembled healthy controls. Differentially expressed genes between transcriptional asthma phenotypes were related to inflammatory and immune responses. Genes in the IL-1 and TNF-α/nuclear factor-κB pathways were overexpressed and correlated with clinical parameters and neutrophilic airway inflammation. Gene expression profiling provides a novel means to investigate the molecular mechanisms and classifications of asthma phenotypes. There are 3 distinct transcriptional phenotypes of asthma that relate to both clinical and inflammatory parameters.

Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort

Publisher: SAGE Publications

Date: 16-11-2020

DOI: 10.1177/0004867419885443

Abstract: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. We performed a case–control genome-wide association study in 429 schizophrenia s les and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. The strongest finding ( p = 2.01 × 10 −6 , odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( p = 2.78 × 10 −6 ). The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error

Publisher: Oxford University Press (OUP)

Date: 07-03-2013

DOI: 10.1093/HMG/DDT116

The power of genetic diversity in genome-wide association studies of lipids

Publisher: Springer Science and Business Media LLC

Date: 09-12-2021

DOI: 10.1038/S41586-021-04064-3

Lack of support for association between the KIF1B rs10492972[C] variant and multiple sclerosis

Publisher: Springer Science and Business Media LLC

Date: 06-2010

DOI: 10.1038/NG0610-469

Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells

Publisher: Springer Science and Business Media LLC

Date: 05-07-2012

DOI: 10.1038/MP.2011.78

Oncostatin m (osm) is increased in asthma with incompletely reversible airflow obstruction

Publisher: Informa UK Limited

Date: 09-11-2009

DOI: 10.3109/01902140902906412

Abstract: Oncostatin M, a unique member of the interleukin (IL)-6 cytokine family, is thought to be involved in airway remodeling. The expression of oncostatin M in the lower airways is unknown. The aim of this study was to measure the sputum expression of oncostatin M in patients with asthma with and without irreversible airflow obstruction. Induced sputum was collected from nonsmoking adults with stable asthma (n = 53), 31 with incomplete reversibility of airflow obstruction. Peripheral blood cells were isolated and stimulated with lipopolysaccharide in 10 participants with asthma and irreversible airflow obstruction. Oncostatin M protein levels were determined in supernatant, whereas RNA was extracted to determine Oncostatin M mRNA expression using real-time polymerase chain reaction (PCR). Oncostatin M mRNA expression and protein levels were significantly higher in the sputum of asthmatics with irreversible airflow obstruction. Sputum oncostatin M levels were highest in people with severe airflow obstruction and were localized to airway neutrophils and macrophages. Peripheral blood neutrophils released more oncostatin M when stimulated with lipopolysaccharide compared with unstimulated neutrophils. Sputum oncostatin M is increased in asthma with irreversible airflow obstruction and is present in airway neutrophils and macrophages. Oncostatin M may link airway inflammation to remodeling in asthma.

Evidence-based medicine in the era of biomarkers: Teaching a new dog old tricks?

Publisher: Springer Science and Business Media LLC

Date: 12-2010

DOI: 10.1038/CLPT.2010.214

Cumulative Small Effect Genetic Markers and the Risk of Colorectal Cancer in Poland, Estonia, Lithuania, and Latvia

Publisher: Hindawi Limited

Date: 2015

DOI: 10.1155/2015/204089

Abstract: The continued identification of new low-penetrance genetic variants for colorectal cancer (CRC) raises the question of their potential cumulative effect among compound carriers. We focused on 6 SNPs (rs380284, rs4464148, rs4779584, rs4939827, rs6983267, and rs10795668), already described as risk markers, and tested their possible independent and combined contribution to CRC predisposition. Material and Methods. DNA was collected and genotyped from 2330 unselected consecutive CRC cases and controls from Estonia (166 cases and controls), Latvia (81 cases and controls), Lithuania (123 cases and controls), and Poland (795 cases and controls). Results. Beyond in idual effects, the analysis revealed statistically significant linear cumulative effects for these 6 markers for all s les except of the Latvian one (corrected P value = 0.018 for the Estonian, corrected P value = 0.0034 for the Lithuanian, and corrected P value = 0.0076 for the Polish s le). Conclusions. The significant linear cumulative effects demonstrated here support the idea of using sets of low-risk markers for delimiting new groups with high-risk of CRC in clinical practice that are not carriers of the usual CRC high-risk markers.

Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function

Publisher: eLife Sciences Publications, Ltd

Date: 15-03-2021

DOI: 10.7554/ELIFE.63115

Abstract: Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise in iduals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug–gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.

Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease

Publisher: Springer Science and Business Media LLC

Date: 13-11-2011

DOI: 10.1038/NG.981

Abstract: Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 in iduals with Kawasaki disease and 9,383 controls from five independent s le collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274 P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis

Publisher: SAGE Publications

Date: 12-12-2014

DOI: 10.1177/1352458513516529

Abstract: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk of developing MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation are recognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure and inherited genetic systems. To identify methylation changes associated with MS, we performed a genome-wide DNA methylation analysis of CD4+ T cells from 30 patients with relapsing–remitting MS and 28 healthy controls using Illumina 450K methylation arrays. A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. After prioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of a major effect CpG island in DRB1 in MS cases ( p FDR 3 × 10 −3 ). In addition, we found 55 non-HLA CpGs that exhibited differential methylation, many of which localise to genes previously linked to MS. Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation to MS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.

Genome-wide association study identifies two novel genomic regions in irritable bowel syndrome

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2014

DOI: 10.1038/AJG.2014.56

The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis

Publisher: Oxford University Press (OUP)

Date: 27-02-2010

DOI: 10.1093/HMG/DDQ090

Abstract: Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300 000 SNPs for 115 of these s les. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10(-12)) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not associated with clinical course or disability. The ANZgene genome wide association screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory molecule, CD40 the other a region on chromosome 12q13-14. The CD40 haplotype associated with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequilibrium. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10(-14)). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Publisher: Wiley

Date: 07-08-2020

DOI: 10.1002/IJC.33206

How to use an article about genetic association - C: What are the results and will they help me in caring for my patients?

Publisher: American Medical Association (AMA)

Date: 21-01-2009

DOI: 10.1001/JAMA.2008.993

Abstract: In the first 2 articles of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies, and we enumerated the major issues in judging the validity of these studies. In this third article, we review the issues relating to the applicability of the results in the clinical situation. How large and precise are the associations? Many genetic effects are expected to be smaller in magnitude than traditional risk factors. Does the genetic association improve predictive power beyond easily measured clinical variables? In some cases, the additional genetic information adds only a small increment in the predictive ability of a diagnostic or prognostic test. What are the absolute vs relative effects? Even if the genetic risk is high in relative terms, the baseline risk may be very low in absolute terms. Is the risk-associated allele likely to be present in my patient? A risk allele may have a strong effect but be rare in a particular ethnic group. Is the patient likely better off knowing the genetic information? Given that genes cannot be modified, one must weigh whether the genetic information is likely to be helpful in planning other health interventions or initiating behavior change.

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Publisher: Springer Science and Business Media LLC

Date: 25-03-2019

DOI: 10.1038/S41588-019-0364-4

Hereditary cancer in clinical practice transfers to BioMed Central

Publisher: Springer Science and Business Media LLC

Date: 26-01-2009

DOI: 10.1186/1897-4287-7-1

Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Publisher: Springer Science and Business Media LLC

Date: 14-11-2018

DOI: 10.1038/S41588-018-0297-3

Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer

Publisher: Springer Science and Business Media LLC

Date: 27-11-2003

DOI: 10.1038/SJ.EJHG.5201064

Integrin β3 Leu33Pro polymorphism increases BRCA1-associated ovarian cancer risk

Publisher: BMJ

Date: 27-02-2007

DOI: 10.1136/JMG.2006.047498

CHAPTER 22. Selenium and Cancer

Publisher: Royal Society of Chemistry

Date: 2015

DOI: 10.1039/9781782622215-00377

Survival of laryngeal cancer patients depending on zinc serum level and oxidative stress genotypes

Publisher: MDPI AG

Date: 10-06-0004

DOI: 10.3390/BIOM11060865

Abstract: Stress contributes to various aspects of malignancy and could influence survival in laryngeal cancer patients. Among antioxidant mechanisms, zinc and the antioxidant enzymes superoxide dismutase 2, catalase and glutathione peroxidase 1 play a major role. The aim of this study was a prospective evaluation of the survival of patients with laryngeal cancer in relation to serum levels of zinc in combination with functional genotype differences of three key antioxidant enzymes. The study group consisted of 300 patients treated surgically for laryngeal cancer. Serum zinc levels and common polymorphisms in SOD2, CAT and GPX1 were analyzed. The risk of death in patients with the lowest zinc levels was increased in comparison with patients with the highest levels. Polymorphisms of antioxidant genes by themselves were not correlated with survival, however, serum zinc level impact on survival was stronger for SOD2 TC/TT and CAT CC variants. GPX1 polymorphisms did not correlate with zinc levels regarding survival. In conclusion, serum zinc concentration appears to be an important prognostic factor for survival of patients diagnosed with laryngeal cancer. When higher zinc levels were correlated with polymorphisms in SOD2 and CAT a further increase in survival was observed.

Intermediate lobe immunoreactivity in a patient with suspected lymphocytic hypophysitis

Publisher: Springer Science and Business Media LLC

Date: 18-01-2013

DOI: 10.1007/S11102-013-0461-9

Abstract: Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. The spectrum of pituitary autoantibodies characterised by indirect immunofluorescence (IF) in these patients has not been substantially defined. The purpose of this study was to determine the spectrum of pituitary autoantibodies in 16 lymphocytic hypophysitis patients. Pituitary sections were prepared from guinea pigs and sera from 16 lymphocytic hypophysitis patients (13 biopsy proven and 3 suspected cases) and 13 healthy controls were evaluated for immunoreactivity to the pituitary tissue by immunofluorescence. A single patient was found to have high titre pituitary autoantibodies against guinea pig pituitary tissue. Immunoreactivity was directed against cells of the intermediate lobe. We present the case report of the patient who is a 24 year old woman that presented with headaches, polyuria and polydipsia. A uniformly enlarged pituitary mass was visible on MRI and a diagnosis of suspected lymphocytic hypophysitis was made. Based on our IF study, we postulate this patient has an autoimmune process directed towards the major cell type in the intermediate lobe, the melanotroph. Pre-adsorption with peptides representing adrenocorticotropic hormone, α-melanocyte stimulating hormone or β-endorphin did not affect the IF signal suggesting our patient's pituitary autoantibodies may target some other product of Proopiomelanocortin (POMC) processing, such as corticotrophin-like intermediate peptide or γ-lipoprotein. Alternatively, the autoantibodies may target a peptide completely unrelated to POMC processing.

Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes.

Publisher: BMJ

Date: 11-1995

DOI: 10.1136/JMG.32.11.909

Abstract: The cancer predisposition in most HNPCC families is believed to be associated with mutations in the human mismatch repair gene homologues hMSH2 and hMLH1. We searched for mutations in our collection of 10 Swiss HNPCC families by sequencing the exons and exon/intron boundaries of the hMSH2 and hMLH1 genes. In four families we found different mutations which are expected to lead to protein truncations of either the hMSH2 or the hMLH1 proteins owing to premature in frame stop codons or splice defects. In two more families we detected mutations leading to an amino acid deletion and an amino acid substitution in an evolutionary conserved residues respectively. None of these mutations has been reported in other families, which is consistent with the notion that HNPCC associated hMSH2 and hMLH1 mutations are heterogeneous and there is no striking founder effect in the Swiss population. Whenever this could be investigated, the presence of the mutations was confirmed in other family members who showed manifestations of HNPCC. Interestingly, an obligate carrier in one of the families developed a brain tumour at the age of 29, histologically verified as a glioblastoma multiforme, which was recently linked to HNPCC in the context of Turcot's syndrome.

Genome-wide significant results identified for plasma apolipoprotein H levels in middle-aged and older adults

Publisher: Springer Science and Business Media LLC

Date: 31-03-2016

DOI: 10.1038/SREP23675

Abstract: Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest s le to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10 −11 ). The results were replicated in an independent cohort, the Hunter Community Study (p 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.

The NOD2 3020insC Mutation and the Risk of Colorectal Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 03-2004

DOI: 10.1158/0008-5472.CAN-03-3791

Abstract: Several predispositions to colorectal cancer have been identified, but little is known about genetic susceptibilities to disease in older persons. Colorectal cancer is a risk in Crohn’s disease and is believed to be associated with an inappropriate inflammatory response. Recently, the NOD2 gene has been associated with Crohn’s disease, which further strengthens the notion that the inflammatory response plays a crucial role in this disease. Several mutations have been identified in the NOD2 gene, which appear with significantly higher frequency in patients with the disease. One such mutation (3020insC) is believed to be clearly causative because it results in a prematurely truncated protein with a predicted reduction in functional efficiency. In this report, we have examined the frequency of the 3020insC mutation in a series of 856 in iduals including 556 patients with colorectal cancer. The frequency of the 3020insC mutation in a consecutive series of 250 non-hereditary nonpolyposis colorectal cancer patients & years of age was significantly elevated compared with the control population (odds ratio, 2.23 P = 0.0046). The results indicate that NOD2 may be a predisposing factor to colorectal cancer characterized by an older average age of disease onset in persons who do not harbor any other genetic predisposition to disease.

Interleukin 1-β responses to bacterial toxins and sudden infant death syndrome

Publisher: Oxford University Press (OUP)

Date: 09-2004

DOI: 10.1016/J.FEMSIM.2004.06.005

Ethnicity, infection and sudden infant death syndrome

Publisher: Oxford University Press (OUP)

Date: 09-2004

DOI: 10.1016/J.FEMSIM.2004.06.007

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Publisher: Springer Science and Business Media LLC

Date: 15-05-2012

DOI: 10.1038/BJC.2012.160

DNA and RNA analyses in detection of genetic predisposition to cancer

Publisher: Springer Science and Business Media LLC

Date: 12-2012

DOI: 10.1186/1897-4287-10-17

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Publisher: Wiley

Date: 03-2020

DOI: 10.1002/GEPI.22288

Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/S1470-2045(21)00189-3

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Publisher: Springer Science and Business Media LLC

Date: 10-2002

DOI: 10.1038/SJ.BJC.6600562

Age of diagnosis of colorectal cancer in HNPCC patients is more complex than that predicted by R72P polymorphism in TP53

Publisher: Wiley

Date: 28-02-2006

DOI: 10.1002/IJC.21661

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer syndrome associated with germline mutations in DNA mismatch repair (MMR) genes. Recently a polymorphism at codon 72 (R72P) in the tumour suppressor gene TP53 has been implicated in the age of disease onset in HNPCC. In this report we have studied a large cohort of HNPCC patients to assess the impact of this polymorphism on disease expression and age of diagnosis of colorectal cancer (CRC). DNA s les from 218 HNPCC mutation positive patients from Australia and Poland were genotyped for the arginine to proline change at codon 72 in the TP53 gene. The association between the polymorphism and disease characteristics (mutation status, disease expression and age of diagnosis of CRC) was tested using Pearson's Chi-square and Kaplan-Meier survival analysis. Our study of Australian and Polish HNPCC patients does not provide evidence for an association between the Arg/Pro (GC) genotype of the R72P polymorphism and age of diagnosis of CRC. The R72P polymorphism was examined in HNPCC patients and found to be not associated with disease development in either the Australian or Polish populations. When gene mutation status (hMLH1 or hMSH2) was included in the analysis some evidence of an affect was observed. The genotyping revealed in the Australian population that the R72P polymorphism was under-represented in the hMSH2 group whereas it was over-represented in the Polish hMSH2 group. A similar trend was observed for hMLH1 in both groups but was not significant. Age of diagnosis of CRC in HNPCC patients is therefore more complex than that predicted by the R72P TP53 polymorphism alone, suggesting an inter-relationship with other genetic and/or environmental factors.

Differential effect of disease-associated ST8SIA2 haplotype on cerebral white matter diffusion properties in schizophrenia and healthy controls

Publisher: Springer Science and Business Media LLC

Date: 22-01-2018

DOI: 10.1038/S41398-017-0052-Z

Abstract: Brain white matter abnormalities are evident in in iduals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 ( ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of in iduals with schizophrenia ( n = 281) and healthy controls ( n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype ( p 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.

Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes

Publisher: Hindawi Limited

Date: 2001

DOI: 10.1002/1098-1004(2001)17:1<52::AID-HUMU6>3.0.CO;2-E

MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer

Publisher: Elsevier BV

Date: 11-2005

DOI: 10.1053/J.GASTRO.2005.09.003

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by heterozygous germline sequence mutations of DNA mismatch repair genes, most frequently MLH1 or MSH2. A novel molecular mechanism for HNPCC has recently been suggested by the finding of in iduals with soma-wide monoallelic hypermethylation of the MLH1 gene promoter. In this study, we determined the frequency and role of germline epimutations of MLH1 in HNPCC. A cohort of 160 probands from HNPCC families who did not harbor germline sequence mutations in the mismatch repair genes were screened for methylation of the MLH1 and EPM2AIP1 promoters by combined bisulfite and restriction analyses. Allelic expression and family transmission of MLH1 were determined using polymorphisms in intron 4 and the 3' untranslated region. One of 160 in iduals had monoallelic MLH1 hypermethylation in peripheral blood, hair follicles, and buccal mucosa, indicative of a soma-wide alteration. Monoallelic transcription of the paternal MLH1 allele was shown using a heterozygous expressed polymorphism within the 3' untranslated region. The hypermethylated allele was maternally transmitted, however, the mother and siblings who inherited the same maternal homologue were unmethylated at MLH1, suggesting the epimutation arose as a de novo event. Germline MLH1 epimutations are functionally equivalent to an inactivating mutation and produce a clinical phenotype that resembles HNPCC. Inheritance of epimutations is weak, so family history is not a useful guide for screening. Germline epimutations should be suspected in younger in iduals without a family history who present with a microsatellite unstable tumor showing loss of MLH1 expression.

Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes

Publisher: Springer Science and Business Media LLC

Date: 15-04-2016

DOI: 10.1007/S10549-016-3775-2

Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

Publisher: Public Library of Science (PLoS)

Date: 18-03-2016

DOI: 10.1371/JOURNAL.PGEN.1005853

Disease expression in Swiss Hereditary Non-Polyposis Colorectal Cancer (HNPCC) kindreds

Publisher: Wiley

Date: 20-06-1997

DOI: 10.1002/(SICI)1097-0215(19970620)74:3<281::AID-IJC8>3.0.CO;2-V

Abstract: The genetics of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) has recently been established and found to be associated with DNA mismatch repair deficiency. As the molecular basis of this syndrome does not appear to predict any particular disease, we compared families selected according to the "Amsterdam" criteria (AC) against families that were selected because of an aggregation of colonic and extracolonic malignancies (EC), all of which have been observed in HNPCC families. A comparison of the 2 groups revealed that there were significant differences between them. Age at disease onset for both groups was 20-30 years younger than in the general population however, a normal age distribution was observed for the AC group whereas for the EC group a bimodal distribution was apparent. The prognosis for both groups together did not differ from that of the general population however, if split, the AC group had a significantly better outcome than the EC group. Furthermore, iding the AC group into hMSH2- and hMLH1-linked families revealed that there was no difference in severity of disease between these 2 groups with respect to survival and mean age of disease onset. Both the AC and EC groups displayed a similar tumour spectrum with a virtually identical tumour distribution. A significant finding was the over-representation, of brain tumours in this family set, which comprised the third most common malignancy after endometrial and stomach cancer.

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.CELL.2018.05.046

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Publisher: Springer Science and Business Media LLC

Date: 05-2019

DOI: 10.1038/S41467-019-10160-W

Abstract: Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Nodular prurigo of the vulva

Publisher: Elsevier BV

Date: 10-2012

DOI: 10.1097/PAT.0B013E328354E006

Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

Publisher: Springer Science and Business Media LLC

Date: 11-06-2021

DOI: 10.1038/S41523-021-00279-9

Abstract: Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2 , including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM , PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN . An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10 −9 ) and missense (OR 1.27, p = 3.96 × 10 −73 ) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and in idually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1 , WRN , PARP2 , CTH and CDK9 . The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

Bladder cancer survival in patients with NOD2 or CDKN2A variants

Publisher: Impact Journals, LLC

Date: 22-04-2022

DOI: 10.18632/ONCOTARGET.28226

Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 26-06-2013

DOI: 10.1038/MP.2012.84

Abstract: Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs N=294), comprising 47.6% of the s le who were impaired across all cognitive measures, and a cognitively spared group (CS N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.

Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication

Publisher: Oxford University Press (OUP)

Date: 08-2013

DOI: 10.1017/S1461145713000035

Abstract: Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6–8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.

Microarrays--identifying molecular portraits for prostate tumors with different Gleason patterns.

Publisher: Humana Press

Date: 2008

DOI: 10.1007/978-1-60327-148-6_8

Abstract: We present in this chapter the combined use of several recently introduced methodologies for the analysis of microarray datasets. These computational techniques are varied in type and very powerful when combined. We have selected a prostate cancer dataset which is available in the public domain to allow for further comparisons with existing methods. The task is to identify biomarkers that correlate with the clinical phenotype of interest, i.e., Gleason patterns 3, 4, and 5. A supervised method, based on the mathematical formalism of (alpha, beta)-k-feature sets (1), is used to select differentially expressed genes. After these "molecular signatures" are identified, we applied an unsupervised method (a memetic algorithm) to order the s les (2). The objective is to maximize a global measure of correlation in the two-dimensional display of gene expression profiles. With the resulting ordering and taxonomy we are able to identify s les that have been assigned a certain Gleason pattern, and have gene expression patterns different from most of the other s les in the group. We reiterate the approach to obtain molecular signatures that produce coherent patterns of gene expression in each of the three Gleason pattern groups, and we analyze the statistically significant patterns of gene expression that seem to be implicated in these different stages of disease.

Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis

Publisher: Oxford University Press (OUP)

Date: 07-2015

DOI: 10.1093/JNCI/DJV178

The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance

Publisher: Wiley

Date: 03-08-2020

DOI: 10.1002/IJC.33224

Multi-trait genome-wide association study identifies novel endometrial cancer risk loci that are associated with obesity or female testosterone levels

Publisher: Cold Spring Harbor Laboratory

Date: 04-08-2021

DOI: 10.1101/2021.08.01.21261455

Abstract: We have performed genetic correlation and Mendelian randomization analyses using publicly available genome-wide association study (GWAS) data to identify endometrial cancer risk factors. These and previously established risk factors of endometrial cancer were then included in a multi-trait Bayesian GWAS analysis to detect endometrial cancer susceptibility variants, identifying three novel loci (7q22.1, 8q24.3 and 16q12.2) two of which were replicated in an independent endometrial cancer GWAS dataset. These loci are hypothesized to affect endometrial cancer risk through altered sex-hormone levels or through effects on obesity. Consistent with this hypothesis, several genes with established roles in these pathways ( CYP11B1, CYP3A7, IRX3 and IRX5 ) were prioritized as candidate endometrial cancer risk genes by interrogation of quantitative trait loci data and chromatin capture assays in endometrial cell lines. The findings of this study identify additional opportunities for hormone treatment and further support weight loss to reduce the risk of developing endometrial cancer. This study prioritizes four genes related to testosterone and obesity as candidate endometrial cancer risk genes, as well as identifies additional opportunities for hormone treatment and further supports weight loss to reduce endometrial cancer risk.

Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: Results from an Australian case-control study

Publisher: Springer Science and Business Media LLC

Date: 27-11-2011

DOI: 10.1007/S10552-010-9688-1

Abstract: To investigate whether maternal coffee and/or tea consumption during the last 6 months of pregnancy was associated with risk of childhood ALL. Data on coffee and tea drinking during pregnancy from 337 case mothers and 697 control mothers were analyzed using unconditional multivariable logistic regression. A meta-analysis of our findings with those of previous studies was also conducted. There was little evidence of an overall association between maternal coffee consumption and risk of ALL: OR 0.89 (95% CI 0.61, 1.30), although there was some suggestion that higher levels of intake might increase the risk in children of non-smoking mothers: OR for 2+ cups/day = 1.44 (95% CI 0.85, 2.42) this was supported by our meta-analysis. Risk was also elevated among cases with chromosomal translocations. The overall OR for maternal tea consumption was 0.82 (95% CI 0.56, 1.18), although the OR for T-cell ALL was 0.21 (95% CI 0.08, 0.51). Among ALL cases with translocations, the ORs for tea consumption tended to be elevated: OR = 1.70 (95% CI 0.79-3.68) for 2+ cups/day. The observed increased risk associated with coffee and tea consumption may be confined to ALL with translocations. These associations should be explored further in large international consortia.

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

Publisher: Springer Science and Business Media LLC

Date: 31-03-2022

DOI: 10.1038/S41588-022-01016-Z

Abstract: We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a s le of ~3 million in iduals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12–16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI’s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.

Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families

Publisher: Wiley

Date: 25-01-2016

DOI: 10.1002/CAM4.628

Fetal growth and risk of childhood acute lymphoblastic leukemia: Results from an australian case-Control study

Publisher: Oxford University Press (OUP)

Date: 28-05-2009

DOI: 10.1093/AJE/KWP117

Abstract: The relation between intrauterine growth and risk of childhood acute lymphoblastic leukemia was investigated in an Australian population-based case-control study that included 347 cases and 762 controls aged <15 years recruited from 2003 to 2006. Information on proportion of optimal birth weight, a measure of the appropriateness of fetal growth, was collected from mothers by questionnaire. Data were analyzed by using logistic regression. Risk of acute lymphoblastic leukemia was positively associated with proportion of optimal birth weight the odds ratio for a 1-standard-deviation increase in proportion of optimal birth weight was 1.18 (95% confidence interval: 1.04, 1.35) after adjustment for the matching variables and potential confounders. This association was also present among children who did not have a high birth weight, suggesting that accelerated growth, rather than high birth weight per se, is associated with risk of acute lymphoblastic leukemia. Similar associations between proportion of optimal birth weight and acute lymphoblastic leukemia were observed for both sexes and across age groups and leukemia subtypes. Results of this study confirm earlier findings of a positive association between rapidity of fetal growth and subsequent risk of acute lymphoblastic leukemia in childhood, and they are consistent with a role for insulin-like growth factors in the causal pathway.

Differing Contributions of Classical Risk Factors to Type 2 Diabetes in Multi-Ethnic Malaysian Populations

Publisher: MDPI AG

Date: 10-12-2018

DOI: 10.3390/IJERPH15122813

Abstract: The prevalence of type 2 diabetes is escalating rapidly in Asian countries, with the rapid increase likely attributable to a combination of genetic and lifestyle factors. Recent research suggests that common genetic risk variants contribute minimally to the rapidly rising prevalence. Rather, recent changes in dietary patterns and physical activity may be more important. This nested case-control study assessed the association and predictive utility of type 2 diabetes lifestyle risk factors in participants from Malaysia, an understudied Asian population with comparatively high disease prevalence. The study s le comprised 4077 participants from The Malaysian Cohort project and included sub-s les from the three major ancestral groups: Malay (n = 1323), Chinese (n = 1344) and Indian (n = 1410). Association of lifestyle factors with type 2 diabetes was assessed within and across ancestral groups using logistic regression. Predictive utility was quantified and compared between groups using the Area Under the Receiver-Operating Characteristic Curve (AUC). In predictive models including age, gender, waist-to-hip ratio, physical activity, location, family history of diabetes and average sleep duration, the AUC ranged from 0.76 to 0.85 across groups and was significantly higher in Chinese than Malays or Indians, likely reflecting anthropometric differences. This study suggests that obesity, advancing age, a family history of diabetes and living in a rural area are important drivers of the escalating prevalence of type 2 diabetes in Malaysia.

Decreased expression of key tumour suppressor microRNAs is associated with lymph node metastases in triple negative breast cancer

Publisher: Springer Science and Business Media LLC

Date: 31-01-2014

DOI: 10.1186/1471-2407-14-51

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Publisher: Springer Science and Business Media LLC

Date: 18-06-2018

DOI: 10.1038/S41588-018-0132-X

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Publisher: American Medical Association (AMA)

Date: 03-2022

DOI: 10.1001/JAMAPSYCHIATRY.2021.3799

Induction and removal of interstrand crosslinks in the ribosomal RNA genes of lymphoblastoid cell lines from patients with Fanconi anemia

Publisher: Elsevier BV

Date: 10-1993

DOI: 10.1016/0027-5107(93)90067-P

Abstract: The repair of interstrand crosslinks has been investigated in Fanconi anemia (FA) and normal cells as there is evidence suggesting that FA patients have a defect in DNA repair. Lymphoblasts were treated with the crosslinking agent mitomycin C (MMC) and the removal of the induced DNA lesions investigated at the level of the actively transcribed ribosomal RNA (rRNA) genes. MMC-induced crosslinks appeared to be a rather stable lesion in the rRNA genes for all cell lines studied. Variable repair efficiencies were found between the different cells lines but they could not be used to distinguish normal cells from FA cells. Therefore, we propose that the specific sensitivity of FA cells towards MMC cannot be directly correlated with a deficient repair in interstrand crosslinks and that probably the complexity of the repair process is greater than previously described.

Exome sequencing of familial adenomatous polyposis-like individuals identifies both known and novel causative genes

Publisher: Wiley

Date: 26-07-2021

DOI: 10.1111/CGE.14029

Abstract: Inherited polyposis syndromes are predominantly caused by pathogenic variants in APC and are linked to familial adenomatous polyposis (FAP). However, after clinical screening, 20%–30% of in iduals diagnosed with FAP do not carry a pathogenic variant in APC (often categorised as FAP‐like). Other known inherited adenomatous polyposis syndromes such as MUTYH , POLD1/E , or NTHL1 ‐associated polyposis only account for, 3 a fraction of the remaining cases. A cohort of 48 in iduals clinically diagnosed with a FAP‐like phenotype was selected based on a strong family history of colorectal cancer and no previous pathogenic variant found in APC and/or MUTYH, by genetic screening. Using whole exome sequencing, FAP‐like patients were found to carry pathogenic variants in MUTYH , APC , POLE and TP53 , as well as DNA‐repair genes and inflammation related genes. Additionally, a comprehensive assessment of copy number variation revealed two loci of interest that appeared to be associated with polyposis risk. In total, 6 out of 48 polyposis were explained through re‐sequencing. This study highlights the potential role of DNA‐repair as well as inflammation‐related variants towards polyp development.

Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas

Publisher: Springer Science and Business Media LLC

Date: 25-06-1998

DOI: 10.1038/SJ.ONC.1201832

Abstract: The 10q25-26 region between the dinucleotide markers D10S587 and D10S216 is deleted in glioblastomas and, as we have recently shown, in low-grade oligodendrogliomas. We further refined somatic mapping on 10q23-tel and simultaneously assessed the role of the candidate tumor suppressor gene PTEN/MMAC1 in glial neoplasms by sequence analysis of eight low-grade and 24 high-grade gliomas. These tumors were selected for partial or complete loss of chromosome 10 based on deletion mapping with increased microsatellite marker density at 10q23-tel. Three out of eight (38%) low-grade and 3/24 (13%) high-grade gliomas exclusively target 10q25-26. We did not find a tumor only targeting 10q23.3, and most tumors (23/32, 72%) showed large deletions on 10q including both regions. The sequence analysis of PTEN/MMAC1 revealed nucleotide alterations in 1/8 (12.5%) low-grade gliomas in a tumor with LOH at l0q21-qtel and in 5/21 (24%) high-grade gliomas displaying LOH that always included 10q23-26. Our refined mapping data point to the 10q25-26 region as the primary target on 10q, an area that also harbors the DMBT1 candidate tumor suppressor gene. The fact that we find hemizygous deletions at 10q25-qtel in low-grade astrocytomas and oligodendrogliomas - two histologically distinct entities of gliomas - suggests the existence of a putative suppressor gene involved early in glial tumorigenesis.

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Publisher: Springer Science and Business Media LLC

Date: 08-01-2019

DOI: 10.1038/S41467-018-07819-1

Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning

Publisher: Springer Science and Business Media LLC

Date: 16-08-2200

DOI: 10.1038/S41380-022-01710-8

Abstract: Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke ( N = 53,637). We identified novel loci in the intronic region of CDH18 , and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent s le. Functional and bioinformatic analyses supported many of these loci and further implicated POC1 . We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Low Blood-As Levels and Selected Genotypes Appears to Be Promising Biomarkers for Occurrence of Colorectal Cancer in Women

Publisher: MDPI AG

Date: 28-08-2021

DOI: 10.3390/BIOMEDICINES9091105

Abstract: In following study we examined whether blood arsenic (As) levels combined with specific polymorphisms in MT1B, GSTP1, ABCB1, NQO1, CRTC3, GPX1, SOD2, CAT, XRCC1, ERCC2 can be used as a marker for the detection of colorectal cancer (CRC) among Polish women. A retrospective case-control study of CRC included 83 CRC cases and 78 healthy controls. From each study participant pre-treatment peripheral blood was collected for As level measurement by inductively coupled–plasma mass spectrometry (ICP-MS). We estimated the odds ratio (OR) of the association between blood-As levels and CRC using multivariable unconditional logistic regression models. A low blood-As level (0.27–0.67 µg/L) was associated with an increased frequency of CRC (OR: 3.69 p = 0.005). This correlation was significantly greater when participants carried particular gene variants: CAT, rs1001179-nonCC (OR: 19.4 p = 0.001) ABCB1 rs2032582–CC (OR: 14.8 p = 0.024) GPX1 rs1050450-CC (OR: 11.6 p = 0.002) and CRTC3 rs12915189-nonGG (OR: 10.3 p = 0.003). Our study provides strong evidence that low blood-As levels are significantly associated with increased CRC occurrence and that particular gene variants significantly enhanced this correlation however, due to the novelty of these findings, we suggest further validation before a definitive statement that the combined effect of low blood-As levels with specific gene polymorphisms is a suitable CRC biomarker.

Genome-wide association analysis identifies six new loci associated with forced vital capacity

Publisher: Springer Science and Business Media LLC

Date: 15-06-2014

DOI: 10.1038/NG.3011

CX3CR1 is dysregulated in blood and brain from schizophrenia patients

Publisher: Elsevier BV

Date: 10-2015

DOI: 10.1016/J.SCHRES.2015.08.010

Abstract: The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by erse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of s le types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N=474) and non-psychiatric control (N=485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N=29) and matched controls (N=31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.

Genome-wide association study identifies five new schizophrenia loci

Publisher: Springer Science and Business Media LLC

Date: 18-09-2011

DOI: 10.1038/NG.940

Exposure to pesticides and the risk of childhood brain tumors

Publisher: Springer Science and Business Media LLC

Date: 05-04-2013

DOI: 10.1007/S10552-013-0205-1

Abstract: Previous research has suggested positive associations between parental or childhood exposure to pesticides and risk of childhood brain tumors (CBT). This Australian case-control study of CBT investigated whether exposures to pesticides before pregnancy, during pregnancy and during childhood, were associated with an increased risk. Cases were recruited from 10 pediatric oncology centers, and controls by random-digit dialing, frequency matched on age, sex, and State of residence. Exposure data were collected by written questionnaires and telephone interviews. Data were analyzed by unconditional logistic regression. The odds ratios (ORs) for professional pest control treatments in the home in the year before the index pregnancy, during the pregnancy, and after the child's birth were 1.54 (95% confidence interval (CI): 1.07, 2.22), 1.52 (95% CI: 0.99, 2.34) and 1.04 (95% CI: 0.75, 1.43), respectively. ORs for treatments exclusively before pregnancy and during pregnancy were 1.90 (95% CI: 1.08, 3.36) and 1.02 (95% CI: 0.35, 3.00), respectively. The OR for the father being home during the treatment was 1.79 (95% CI: 0.85, 3.80). The OR for paternal occupational exposure in the year before the child's conception was 1.36 (95% CI: 0.66, 2.80). ORs for prenatal home pesticide exposure were elevated for low- and high-grade gliomas effect estimates for other CBT subtypes varied and lacked precision. These results suggest that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased CBT risk. It may be advisable for both parents to avoid pesticide exposure during this time.

Modifier genes and Lynch syndrome: some considerations

Publisher: Springer Science and Business Media LLC

Date: 10-09-2022

DOI: 10.1186/S13053-022-00240-2

Abstract: Lynch Syndrome (LS) is a highly variable entity with some patients presenting at very young ages with malignancy whereas others may never develop a malignancy yet carry an unequivocal genetic predisposition to disease. The most frequent LS malignancy remains colorectal cancer, a disease that is thought to involve genetic as well as environmental factors in its aetiology. Environmental insults are undeniably associated with cancer risk, especially those imparted by such activities as smoking and excessive alcohol consumption. Notwithstanding, in an inherited predisposition the expected exposures to an environmental insult are considered to be complex and require knowledge about the respective exposure and how it might interact with a genetic predisposition. Typically, smoking is one of the major confounders when considering environmental factors that can influence disease expression on a background of significant genetic risk. In addition to environmental triggers, the risk of developing a malignancy for people carrying an inherited predisposition to disease can be influenced by additional genetic factors that do not necessarily segregate with a disease predisposition allele. The purpose of this review is to examine the current state of modifier gene detection in people with a genetic predisposition to develop LS and present some data that supports the notion that modifier genes are gene specific thus explaining why some modifier gene studies have failed to identify associations when this is not taken into account.

Genetically informed precision drug repurposing for lung function and implications for respiratory infection

Publisher: Cold Spring Harbor Laboratory

Date: 26-06-2020

DOI: 10.1101/2020.06.25.20139816

Abstract: Impaired lung function is associated with significant morbidity and mortality. Restrictive and obstructive lung disorders are a large contributor to decreased lung function, as well as the acute impact of infection. Measures of pulmonary function are heritable, and thus, we sought to utilise genomics to propose novel drug repurposing candidates which could improve respiratory outcomes. Lung function measures were found to be genetically correlated with metabolic and hormone traits which could be pharmacologically modulated, with a causal effect of increased fasting glucose on diminished lung function supported by latent causal variable models and Mendelian randomisation. We developed polygenic scores for lung function specifically within pathways with known drug targets to prioritise in iduals who may benefit from particular drug repurposing opportunities, accompanied by transcriptome-wide association studies to identify drug-gene interactions with potential lung function increasing modes of action. These drug repurposing candidates were further considered relative to the host-viral interactome of three viruses with associated respiratory pathology (SARS-CoV2, influenza, and human adenovirus). We uncovered an enrichment amongst glycaemic pathways of human proteins which putatively interact with virally expressed SARS-CoV2 proteins, suggesting that antihyperglycaemic agents may have a positive effect both on lung function and SARS-CoV2 progression.

Biobank classification in an australian setting

Publisher: Mary Ann Liebert Inc

Date: 06-2015

DOI: 10.1089/BIO.2015.0007

Abstract: In 2011, Watson and Barnes proposed a schema for classifying biobanks into 3 groups (mono-, oligo-, and poly-user), primarily based upon biospecimen access policies. We used results from a recent comprehensive survey of cancer biobanks in New South Wales, Australia to assess the applicability of this biobank classification schema in an Australian setting. Cancer biobanks were identified using publically available data, and by consulting with research managers. A comprehensive survey was developed and administered through a face-to-face setting. Data were analyzed using Microsoft Excel™ 2010 and IBM SPSS Statistics™ version 21.0. The cancer biobank cohort (n=23) represented 5 mono-user biobanks, 7 oligo-user biobanks, and 11 poly-user biobanks, and was analyzed as two groups (mono-/oligo- versus poly-user biobanks). Poly-user biobanks employed significantly more full-time equivalent staff, and were significantly more likely to have a website, share staff between biobanks, access governance support, utilize quality control measures, be aware of biobanking best practice documents, and offer staff training. Mono-/oligo-user biobanks were significantly more likely to seek advice from other biobanks. Our results further delineate a biobank classification system that is primarily based on access policy, and demonstrate its relevance in an Australian setting.

BRCA1-associated breast and ovarian cancer risks in Poland: No association with commonly studied polymorphisms

Publisher: Springer Science and Business Media LLC

Date: 10-04-2010

DOI: 10.1007/S10549-009-0390-5

Abstract: Polymorphisms in genes involved in DNA repair, steroid hormone biosynthesis/metabolism/signaling, folate metabolism as well as cell growth are prime candidates for possible associations with breast and ovarian cancer risk in women with an inherited predisposition. We investigated 29 polymorphisms in 20 genes encoding key proteins of the above four biological pathways for their breast and ovarian cancer risk modifying effect in Polish women harboring BRCA1 founder mutations. Of the analyzed genes, ERCC2, XRCC1, XRCC2, XRCC3 and Lig4 participate in DNA repair, TP53 in cell cycle check point control, AIB1, AR, COMT, CYP11A1, CYP17A1, CYP19A1, HSD17 and PGR in steroid hormone biosynthesis/metabolism/signaling, TYMS in folate metabolism and HER2, IL6, LRP1, TGFB and TGFBR1 affect cell growth. Using validated methods, we genotyped 319 breast cancer cases, 146 ovarian cancer cases and 290 unaffected controls, all of whom harbored one of three causative mutations in BRCA1. Our results revealed no association of any of the investigated polymorphisms with BRCA1-associated breast or ovarian cancer risk. Thus, it appears that these polymorphisms do not influence disease risk in Polish women carrying one of the three common BRCA1 founder mutations.

Folate pathway gene polymorphisms and risk of childhood brain tumors: Results from an Australian case-control study

Publisher: American Association for Cancer Research (AACR)

Date: 31-05-2015

DOI: 10.1158/1055-9965.EPI-14-1248

Abstract: Background: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT) polymorphisms in folate pathway genes could modify this association or directly influence CBT risk. Methods: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case–control study in Australia (2005–2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C& T, MTHFR 1298A& C, MTRR 66A& G, MTR 2756A& G, MTR 5049C& A, and CBS 2199 T& C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case–parent trio analyses were also undertaken. Results: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48–1.07] 0.54 (95% CI, 0.34–0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively). Conclusions: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation these results are novel and require replication. Impact: The possible interaction between folic acid supplementation and MTRR 66A& G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT. Cancer Epidemiol Biomarkers Prev 24(6) 931–7. ©2015 AACR.

DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients

Publisher: Springer Science and Business Media LLC

Date: 27-09-2016

DOI: 10.1038/SREP33435

Abstract: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no targeted treatment available. Our previous study identified 38 TNBC-specific genes with altered expression comparing tumour to normal s les. This study aimed to establish whether DNA methylation contributed to these expression changes in the same cohort as well as disease progression from primary breast tumour to lymph node metastasis associated with changes in the epigenome. We obtained DNA from 23 primary TNBC s les, 12 matched lymph node metastases, and 11 matched normal adjacent tissues and assayed for differential methylation profiles using Illumina HumanMethylation450 BeadChips. The results were validated in an independent cohort of 70 primary TNBC s les. The expression of 16/38 TNBC-specific genes was associated with alteration in DNA methylation. Novel methylation changes between primary tumours and lymph node metastases, as well as those associated with survival were identified. Altered methylation of 18 genes associated with lymph node metastasis were identified and validated. This study reveals the important role DNA methylation plays in altered gene expression of TNBC-specific genes and lymph node metastases. The novel insights into progression of TNBC to secondary disease may provide potential prognostic indicators for this hard-to-treat breast cancer subtype.

Integrin αvβ6-associated ERK2 mediates MMP-9 secretion in colon cancer cells

Publisher: Springer Science and Business Media LLC

Date: 07-2002

DOI: 10.1038/SJ.BJC.6600480

VariantSpark: Population scale clustering of genotype information

Publisher: Springer Science and Business Media LLC

Date: 12-2015

DOI: 10.1186/S12864-015-2269-7

Can selenium levels act as a marker of colorectal cancer risk?

Publisher: Springer Science and Business Media LLC

Date: 29-04-2013

DOI: 10.1186/1471-2407-13-214

Narrowing the critical region for overgrowth within 13q14.2-q14.3 microdeletions

Publisher: Elsevier BV

Date: 11-2015

DOI: 10.1016/J.EJMG.2015.10.006

Abstract: Large chromosomal deletions from 13q13.3 to 13q21.3 have previously been associated with overgrowth. We present two patients with deletions at 13q14.2q14.3 who have macrocephaly, tall stature relative to their parents, cardiac phenotypes, and intellectual disability. This report narrows the critical region for tall stature, macrocephaly, and possibly cardiac disease.

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding

Publisher: Elsevier BV

Date: 06-2016

DOI: 10.1016/J.AJHG.2016.04.012

Detecting genotyping error using measures of degree of hardy-weinberg disequilibrium

Publisher: Walter de Gruyter GmbH

Date: 06-01-2010

DOI: 10.2202/1544-6115.1463

Abstract: Tests for Hardy-Weinberg equilibrium (HWE) have been used to detect genotyping error, but those tests have low power unless the s le size is very large. We assessed the performance of measures of departure from HWE as an alternative way of screening for genotyping error. Three measures of the degree of disequilibrium (alpha, ,D, and F) were tested for their ability to detect genotyping error of 5% or more using simulations and a real dataset of 184 children with leukemia genotyped at 28 single nucleotide polymorphisms. The simulations indicate that all three disequilibrium coefficients can usefully detect genotyping error as judged by the area under the Receiver Operator Characteristic (ROC) curve. Their discriminative ability increases as the error rate increases, and is greater if the genotyping error is in the direction of the minor allele. Optimal thresholds for detecting genotyping error vary for different allele frequencies and patterns of genotyping error but allele frequency-specific thresholds can be nominated. Applying these thresholds would have picked up about 90% of genotyping errors in our actual dataset. Measures of departure from HWE may be useful for detecting genotyping error, but this needs to be confirmed in other real datasets.

Effects of gender, cytokine gene polymorphisms and environmental factors on inflammatory responses

Publisher: SAGE Publications

Date: 27-11-2014

DOI: 10.1177/1753425914553645

Abstract: Previous studies have indicated that cytokine gene polymorphisms of Indigenous Australians were predominantly associated with strong pro-inflammatory responses. We tested the hypothesis that cells of donors with genetic profiles of inflammatory cytokine single nucleotide polymorphisms (SNPs) similar to Indigenous Australians produce higher pro-inflammatory responses. PBMCs from 14 donors with genetic profiles for a high risk of strong pro-inflammatory responses and 14 with low-risk profiles were stimulated with endotoxin and effects of gender, IFN-γ, cigarette smoke extract (CSE) and testosterone on cytokine responses analysed. Cytokines were calculated from standard curves (Luminex 2.3 software). No significant differences were associated with SNP profile alone. Lower pro-inflammatory responses were observed for cells from males with low- or high-risk profiles. For cells from females with high-risk profiles, anti-inflammatory IL-10 responses were significantly reduced. There was no effect of testosterone levels on responses from males. For females, results from IFN-γ-treated cells showed positive correlations between testosterone levels and IL-1β responses to endotoxin for both risk groups and TNF-α for the high-risk group. If interactions observed among CSE, IFN-γ, genetic background and testosterone reflect those in vivo, these might contribute to increased incidences of hospitalisations for infectious diseases among Indigenous women.

Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia

Publisher: Elsevier BV

Date: 02-2006

DOI: 10.1016/J.SCHRES.2005.11.012

Abstract: Schizophrenia is a heterogenous disorder that is phenomenologically characterised by a combination of negative, positive, and cognitive symptoms with variable expression in the course of illness. Here, we investigated differential gene expression in relation to age to address the heterogeneity of this disorder We used 6000 gene cDNA microarrays to generate gene expression profiles from peripheral blood lymphocytes from 14 in iduals with schizophrenia and 14 non-psychiatric controls. Genes showing altered expression were identified and 18 genes with brain-related functions were altered, 4 of which, endothelial differentiation gene 2 (Edg-2), ezrin-radixin-moesin phosphoprotein 50 (EBP50), Myc-associated zinc finger protein (MAZ) and Tumor Necrosis Factor Receptor 2 (TNFR2), were confirmed by relative real-time PCR. Dendrograms were constructed using genes that showed significantly different expression (p<0.05) between groups based on median split of age iding the matched pairs into distinct subclasses. Our findings suggest that distinct gene expression profiles in peripheral blood lymphocytes associated with schizophrenia phenotypes may provide a first step towards the biological classification of schizophrenia subtypes. The validity of this approach may lead to better methods of defining this enigmatic disease.

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Publisher: Springer Science and Business Media LLC

Date: 02-09-2012

DOI: 10.1038/NG.2397

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 09-2017

DOI: 10.1161/HYPERTENSIONAHA.117.09438

Abstract: Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry in iduals and sought significant evidence for independent replication in a further 228 245 in iduals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . Combining large whole-blood gene expression resources totaling 12 607 in iduals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Genome-wide association study identifies a common variant associated with risk of endometrial cancer

Publisher: Springer Science and Business Media LLC

Date: 17-04-2011

DOI: 10.1038/NG.812

The expression of Dicer and Drosha in matched normal tissues, tumours and lymph node metastases in triple negative breast cancer

Publisher: Springer Science and Business Media LLC

Date: 11-04-2014

DOI: 10.1186/1471-2407-14-253

Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker

Publisher: Springer Science and Business Media LLC

Date: 04-12-2018

DOI: 10.1038/S41467-018-07214-W

Abstract: Epigenetic reprogramming in cancer genomes creates a distinct methylation landscape encompassing clustered methylation at regulatory regions separated by large intergenic tracks of hypomethylated regions. This methylation landscape that we referred to as Methylscape is displayed by most cancer types, thus may serve as a universal cancer biomarker. To-date most research has focused on the biological consequences of DNA Methylscape changes whereas its impact on DNA physicochemical properties remains unexplored. Herein, we examine the effect of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to detect the Methylscape biomarker. We find that DNA polymeric behaviour is strongly affected by differential patterning of methylcytosine, leading to fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes. We exploit these Methylscape differences to develop simple, highly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer. These assays are quick, i.e., analysis time ≤10 minutes, and require minimal s le preparation and small DNA input.

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 08-2002

DOI: 10.1007/S00432-002-0361-2

Abstract: Identification of germline mutations in mismatch repair genes is increasingly being used to guide clinical practice in hereditary non-polyposis colon cancer. The aim of this study was to retrospectively assess the clinical utility of immunostaining and microsatellite instability testing in a group of in iduals in whom germline testing of hMSH2 and hMLH1 had already been performed. In iduals were identified from the records of family cancer clinics. A total of thirty-eight tumour blocks were retrieved from 28 kindreds. DNA was extracted and PCR lification of six microsatellite markers was performed. Immunostaining was used to examine the expression of hMSH2 and hMLH1 protein. Of the 32 assessable tumours, 24 (75%) showed microsatellite instability. Most of the MSI-H cancers (92%) failed to express either hMLH1 or hMSH2. Deleterious germline mutations were identified in the proband in 12 of 28 families. Missense mutations were identified in 11 cases and no mutations in six probands. The use of germline genetic testing is indicated for a highly selected group of in iduals. MSI testing and immunostaining are extremely useful tools which significantly improve the clinical interpretation of germline results. Ambiguity regarding the significance of missense mutations in hereditary bowel cancer suggests that these findings should be interpreted with caution.

Transcriptomic abnormalities in peripheral blood in bipolar disorder, and discrimination of the major psychoses

Publisher: Elsevier BV

Date: 03-2020

DOI: 10.1016/J.SCHRES.2019.07.036

Are Myocardial Infarction–Associated Single-Nucleotide Polymorphisms Associated With Ischemic Stroke?

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 04-2012

DOI: 10.1161/STROKEAHA.111.632075

Abstract: Ischemic stroke (IS) shares many common risk factors with coronary artery disease (CAD). We hypothesized that genetic variants associated with myocardial infarction (MI) or CAD may be similarly involved in the etiology of IS. To test this hypothesis, we evaluated whether single-nucleotide polymorphisms (SNPs) at 11 different loci recently associated with MI or CAD through genome-wide association studies were associated with IS. Meta-analyses of the associations between the 11 MI-associated SNPs and IS were performed using 6865 cases and 11 395 control subjects recruited from 9 studies. SNPs were either genotyped directly or imputed in a few cases a surrogate SNP in high linkage disequilibrium was chosen. Logistic regression was performed within each study to obtain study-specific βs and standard errors. Meta-analysis was conducted using an inverse variance weighted approach assuming a random effect model. Despite having power to detect odds ratio of 1.09–1.14 for overall IS and 1.20–1.32 for major stroke subtypes, none of the SNPs were significantly associated with overall IS and/or stroke subtypes after adjusting for multiple comparisons. Our results suggest that the major common loci associated with MI risk do not have effects of similar magnitude on overall IS but do not preclude moderate associations restricted to specific IS subtypes. Disparate mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events.

Capturing all disease-causing mutations for clinical and research use: Toward an effortless system for the Human Variome Project

Publisher: Elsevier BV

Date: 12-2009

DOI: 10.1097/GIM.0B013E3181C371C5

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Publisher: Bioscientifica

Date: 10-2015

DOI: 10.1530/ERC-15-0319

Abstract: Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1 . Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P =1.86×10 −5 ), which was stronger for cancers of endometrioid subtype ( P =3.76×10 −6 ). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1 , and eQTL analysis found that rs79575945 was associated with expression of SYNE1 , a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1 , at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.

IL-2 Approval Recommended by FDA Panel

Publisher: Oxford University Press (OUP)

Date: 19-02-1992

DOI: 10.1093/JNCI/84.4.226-A

A Transcription Factor Map as Revealed by a Genome- Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

Publisher: Public Library of Science (PLoS)

Date: 12-2010

DOI: 10.1371/JOURNAL.PONE.0014176

The Architecture of Risk for Type 2 Diabetes: Understanding Asia in the Context of Global Findings

Publisher: Hindawi Limited

Date: 2014

DOI: 10.1155/2014/593982

Abstract: The prevalence of Type 2 diabetes is rising rapidly in both developed and developing countries. Asia is developing as the epicentre of the escalating pandemic, reflecting rapid transitions in demography, migration, diet, and lifestyle patterns. The effective management of Type 2 diabetes in Asia may be complicated by differences in prevalence, risk factor profiles, genetic risk allele frequencies, and gene-environment interactions between different Asian countries, and between Asian and other continental populations. To reduce the worldwide burden of T2D, it will be important to understand the architecture of T2D susceptibility both within and between populations. This review will provide an overview of known genetic and nongenetic risk factors for T2D, placing the results from Asian studies in the context of broader global research. Given recent evidence from large-scale genetic studies of T2D, we place special emphasis on emerging knowledge about the genetic architecture of T2D and the potential contribution of genetic effects to population differences in risk.

Identification of nine new susceptibility loci for endometrial cancer

Publisher: Springer Science and Business Media LLC

Date: 09-08-2018

DOI: 10.1038/S41467-018-05427-7

Abstract: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins ( SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

Gene expression profiling in familial adenomatous polyposis adenomas and desmoid disease

Publisher: Springer Science and Business Media LLC

Date: 2007

DOI: 10.1186/1897-4287-5-2-79

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in theZNF804APathway

Publisher: American Medical Association (AMA)

Date: 07-2014

DOI: 10.1001/JAMAPSYCHIATRY.2014.528

Genetic association of refractive error and axial length with 15q14 but not 15q25 in the blue mountains eye study cohort

Publisher: Elsevier BV

Date: 02-2013

DOI: 10.1016/J.OPHTHA.2012.08.006

Abstract: Myopia is a common complex condition influenced by genetic and environmental factors. Two recent genome-wide association studies have identified loci on chromosomes 15q25 and 15q14 associated with refractive error in Caucasian populations. Our study aimed to assess the association of these 2 loci with refractive error and ocular biometric measures in an independent ethnically matched Caucasian cohort. Genetic association study using unrelated in iduals. Blue Mountains Eye Study (BMES) cohort. A total of 1571 in iduals were included in this study. Single nucleotide polymorphism (SNP) genotype data were collected from the BMES cohort as part of the Wellcome Trust Case Control Consortium 2. Imputation was performed using MACH version 1.1.16, and statistical analysis was conducted using PLINK. Association tests were performed at both loci using refractive error (spherical equivalent), axial length, corneal curvature, and anterior chamber depth as the phenotypes. Refractive error, axial length, corneal curvature, and anterior chamber depth. A total of 1571 in iduals were available from the BMES for analysis. A statistically significant association for refractive error was evident for SNPs at the 15q14 locus, with P values ranging from 1.5 × 10(-2) at rs685352 to 6.4 × 10(-4) at rs560764, whereas association could not be confirmed for SNPs at the 15q25 locus, with P values ranging from 8.0 × 10(-1) to 6.4 × 10(-1). Ocular biometric analysis revealed that axial length was the most likely trait underlying the refractive error association at the 15q14 locus for SNPs rs560766 (P=0.0054), rs634990 (P=0.0086), and rs8032019 (P=0.0081). Our results confirm the association with refractive error at the 15q14 locus but do not support the association observed at the 15q25 locus. Axial length seemed to be a major parameter at the 15q14 locus, underscoring the importance of this locus in myopia and future clinical treatment.

Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing

Publisher: Wiley

Date: 20-01-2017

DOI: 10.1002/1878-0261.12023

Association of Extracolonic Manifestations of Familial Adenomatous Polyposis with Acetylation Phenotype in a Large FAP Kindred

Publisher: Wiley

Date: 1997

DOI: 10.1159/000484730

STK11 status and intussusception risk in Peutz-Jeghers syndrome.

Publisher: BMJ

Date: 08-2006

DOI: 10.1136/JMG.2005.040535

Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1

Publisher: Informa UK Limited

Date: 19-05-2017

DOI: 10.1080/08916934.2017.1332183

Abstract: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity

Publisher: Springer Science and Business Media LLC

Date: 12-2022

DOI: 10.1186/S13148-022-01397-2

Abstract: The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene–environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker. We conducted an epigenome-wide association study between 235 females with mild ( n = 119) or severe ( n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis using ToppGene . We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance. Females with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity. RMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.

Smoking Related Cancers and Loci at Chromosomes 15q25, 5p15, 6p22.1 and 6p21.33 in the Polish Population

Publisher: Public Library of Science (PLoS)

Date: 22-09-2011

DOI: 10.1371/JOURNAL.PONE.0025057

Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and risk of childhood brain tumors

Publisher: Informa UK Limited

Date: 04-06-2014

DOI: 10.1080/01635581.2014.916326

Abstract: Childhood brain tumors (CBT) are the second most common childhood cancers, yet their etiology is largely unknown. We investigated whether maternal gestational intake of folate and vitamins B6 and B12 was associated with CBT risk in a nationwide case-control study conducted 2005-2010. Case children 0-14 years were recruited from all 10 Australian pediatric oncology centers. Control children were recruited by national random digit dialing, frequency matched to cases on age, sex, and state of residence. Dietary intake was ascertained using food frequency questionnaires and adjusted for total energy intake. Data from 293 case and 726 control mothers were analyzed using unconditional logistic regression. The odds ratio (OR) for the highest versus lowest tertile of folate intake was 0.70 [95% confidence interval (CI): 0.48, 1.02]. The ORs appeared lower in mothers who drank alcohol during pregnancy (OR = 0.45, 95% CI: 0.22, 0.93), mothers who took folic acid (OR = 0.67, 95% CI: 0.42, 1.06) or B6/B12 supplements (OR = 0.51, 95% CI: 0.25, 1.06) and in children younger than 5 years (OR = 0.50, 95% CI: 0.27, 0.93). These findings are consistent with folate's crucial role in maintenance of genomic integrity and DNA methylation. Dietary intake of B6 and B12 was not associated with risk of CBT.

Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families.

Publisher: BMJ

Date: 11-1997

DOI: 10.1136/JMG.34.11.884

Abstract: In this study we investigated 45 German breast/ovarian cancer families for germline mutations in the BRCA1 gene. We identified four germline mutations in three breast cancer families and in one breast-ovarian cancer family. among these were one frameshift mutation, one nonsense mutation, one novel splice site mutation, and one missense mutation. The missense mutation was also found in 2.8% of the general population, suggesting that it is not disease associated. The average age of disease onset in those families harbouring causative mutations was between 32.3 and 37.4 years, whereas the family harbouring the missense mutation had an average age of onset of 51.2 years. These findings show that BRCA1 is implicated in a small fraction of breast/ovarian cancer families suggesting the involvement of another susceptibility gene(s).

BRCA1 mutations in a selected series of breast/ovarian cancer patients.

Publisher: BMJ

Date: 09-1996

DOI: 10.1136/JMG.33.9.721

Abstract: Germline mutations in the BRCA1 gene have been associated with familial breast/ ovarian cancer in large families showing high penetrance of the disease. Little is known, however, about the contribution of BRCA1 mutations to breast/ovarian cancer in small families with few affected members or in isolated early onset cases. Therefore we examined the BRCA1 gene in 63 breast/ovarian cancer patients who either came from small families with as few as one affected first degree relative, or in patients who had no family history but had developed breast cancer under 40 years of age. Using the protein truncation test, we were able to identify three unique BRCA1 germline mutations (4.8%). Two of the probands had only one affected first degree and several second degree relatives and the third had three affected first degree relatives including two sisters who, when tested, were also found to carry the mutation. There was no family history of ovarian cancer in any of the three families.

Multi-trait genome-wide association study of opioid addiction:OPRM1and Beyond

Publisher: Cold Spring Harbor Laboratory

Date: 16-09-2021

DOI: 10.1101/2021.09.13.21263503

Abstract: Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant in OPRM1 , has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective s le size of 88,114 in iduals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r g 0.9). We observed the strongest evidence to date for OPRM1 : lead SNP rs9478500 ( p =2.56×10 −9 ). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN . Variants within these loci appear to be pleiotropic for addiction and related traits.

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Publisher: Springer Science and Business Media LLC

Date: 10-2022

DOI: 10.1186/S13053-022-00241-1

Abstract: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes ( path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females for path_MSH2 50% and 39% for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27% 34% and 23% 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were 1% in all retrospective groups. Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Publisher: Cold Spring Harbor Laboratory

Date: 18-09-2020

DOI: 10.1101/2020.09.17.20187054

Abstract: Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippoc us. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Association between endometriosis and the interleukin 1A (IL1A) locus

Publisher: Oxford University Press (OUP)

Date: 21-10-2015

DOI: 10.1093/HUMREP/DEU267

A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology

Publisher: S. Karger AG

Date: 2009

DOI: 10.1159/000200093

Abstract: Children with intellectual disability, dysmorphic features, malformations and/or growth abnormalities frequently display normal karyotypes. Recent studies have shown that genome-wide single nucleotide polymorphism (SNP) arrays can be effective in detecting abnormalities involving copy number variation (CNV), deletions, duplications and loss of heterozygosity (LOH) that routine cytogenetic tests fail to identify. Five patients with various degrees of intellectual disability and/or dysmorphic features and other malformations were whole-genome genotyped using the Human-1 Genotyping BeadChip – Exon-Centrix 100K SNP arrays (Illumina). All patients had undergone routine cytogenetic testing four patients had normal karyotypes, while one patient had an apparently balanced complex translocation involving chromosomes 1q25, 1q32, 2q23, 7q22 and 16q24. We detected deletions on chromosome 1q44 and 13q31.1 in one patient, and LOH of the entire chromosome 2 in another patient, both with cytogenetically normal karyotypes. The patient with the complex translocation had a deletion on chromosome 7q22.2-22.3, which is in conjunction with one of the translocation breakpoints. Our findings provide further evidence of there being a critical region for the development of microcephaly and corpus callosum abnormalities in children with distal 1q deletions. We have also shown that apparently balanced complex translocations might not be balanced at the DNA level, and we report the fourth case of paternal uniparental disomy of chromosome 2. The results of this study suggest that it may be desirable to investigate idiopathic mental retardation using genome-wide SNP arrays, in conjunction with other cytogenetic and molecular techniques.

Development of an experimental model for assessing the effects of cigarette smoke and virus infections on inflammatory responses to bacterial antigens

Publisher: SAGE Publications

Date: 17-10-2013

DOI: 10.1177/1753425913503893

Abstract: Interactions among major risk factors associated with bacterial infections were assessed in a model system using surrogates for virus infection IFN-g, and exposure to cigarette smoke cigarette smoke extract (CSE), nicotine and cotinine. Cytokine responses elicited by LPS from THP-1 cells in the presence of these components, or combinations of components, were assessed by multiplex bead assay, i.e. IL-1β, IL-6, IL-8, IL-10, TNF-α and IFN-γ. IFN-γ-priming significantly increased pro-inflammatory cytokines induced by LPS. CSE suppressed production of pro-inflammatory cytokines IL-1β, TNF-α and IFN-γ, but enhanced production of IL-8. Nicotine and cotinine suppressed all cytokine responses. In combination, IFN-γ masked the inhibitory effects of CSE. In relation to the objectives of the study, we concluded that (a) IFN-γ at biologically relevant concentrations significantly enhanced pro-inflammatory responses (b) CSE, nicotine and cotinine dysregulated the inflammatory response and that the effects of CSE were different from those of the in idual components, nicotine and cotinine (c) when both IFN-γ and CSE were present, IFN-γ masked the effect of CSE. There is a need for clinical investigations on the increase in IL-8 responses in relation to exposure to cigarette smoke and increased pro-inflammatory responses in relation to recent viral infection.

Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility

Publisher: Cold Spring Harbor Laboratory

Date: 04-12-2020

DOI: 10.1101/2020.12.03.20243758

Abstract: Genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic susceptibility loci. To identify candidate endometrial cancer susceptibility genes, we have performed the first transcriptome-wide association study (TWAS) of endometrial cancer. For this analysis, we have used the largest endometrial cancer GWAS and gene expression from 48 tissues to maximise statistical power. We used colocalisation analysis to prioritise seven candidate susceptibility genes, including CYP19A1 , which wes previously established as an endometrial cancer susceptibility gene. Notably, one of the candidate susceptibility genes was located at 17q24.2, a potentially novel risk locus for endometrial cancer. Using phenome-wide association analysis, candidate susceptibility genes were found to associate with traits related to endometrial cancer risk factors, in addition to other clinical phenotypes that may provide novel risk factors. TWAS data were also used to perform drug repurposing analysis and identified 14 compounds two of these are tubulin inhibitors, a drug class used to treat advanced endometrial cancer. In summary, this study has revealed biologically relevant endometrial cancer susceptibility genes, providing insights into endometrial cancer aetiology and avenues for the development of new treatments.

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Publisher: Elsevier BV

Date: 12-2011

DOI: 10.1016/S0140-6736(11)61049-0

Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes

Publisher: Oxford University Press (OUP)

Date: 12-02-2013

DOI: 10.1093/HMG/DDT062

Abstract: Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in in iduals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 s les and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10(-11), OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools this result has important implications for the design of future fine-mapping studies.

CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC

Publisher: Springer Science and Business Media LLC

Date: 29-04-2021

DOI: 10.1186/S13053-021-00183-0

Abstract: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For ex le attenuated forms of the disease are associated with pathogenic variants at the 5’ and 3’ ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36 . We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected in iduals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

Xeroderma pigmentosum-Cockayne syndrome complex in two patients: Absence of slun tumors despite severe deficiency of DNA excision repair

Publisher: Elsevier BV

Date: 11-1993

DOI: 10.1016/0190-9622(93)70263-S

Abstract: Two brothers had a complex combination of two DNA repair disorders: Cockayne syndrome and xeroderma pigmentosum. This rare combination has previously been observed in only two other patients. The clinical signs shared by these two brothers and the two other previously described patients include severe sun sensitivity, freckling, diminished stature, hearing and movement impairment, and neurologic degeneration. Although defective UV-induced unscheduled DNA synthesis has been demonstrated (5% of normal), no skin cancers have appeared in these 38- and 41-year-old brothers, whereas skin cancers developed at a relatively early age in the two previously described patients who also had defective UV-induced unscheduled DNA synthesis.

Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin

Publisher: American Association for Cancer Research (AACR)

Date: 15-03-2008

DOI: 10.1158/1078-0432.CCR-07-1422

Abstract: Purpose: Metastatic melanoma is largely unresponsive to DNA-damaging chemotherapy agents, although WTp53 is frequently detected. Several isoforms of p53 have been discovered, some of which inhibit p53 function. We therefore examined whether p53 isoforms were present in melanoma and whether they may contribute to aberrant p53 function in melanoma. Experimental Design: We studied the expression and subcellular localization of p53 and its isoforms in a panel of human melanoma cell lines using Western blot, two-dimensional electrophoresis, and reverse transcription-PCR. We also characterized the relationship between the expression of p53, p53 isoforms, and p53 target genes following treatment with the DNA-damaging agent cisplatin. Results: We report that p53β and Δ40p53 were expressed in the majority of melanoma cell lines at the mRNA level, but were absent or expressed at low levels in fibroblasts and melanocytes, suggesting that their expression may play a role in melanoma development. Analysis by two-dimensional gel electrophoresis revealed that p53β was expressed at the protein level in melanoma cells. Both p53 and the small molecular weight forms of p53 were aberrantly expressed between the nuclear and cytosolic fractions of melanoma cell lines, compared with normal fibroblasts. Treatment with cisplatin had differential effects on WTp53 and the small molecular weight form of p53 that were cell line dependent. Δ40p53 was shown to inhibit, whereas p53β was shown to enhance, p53-dependent transcription of p21 and PUMA. Conclusions: p53β and Δ40p53 are expressed in melanoma and this may have important implications for understanding resistance of melanoma to DNA-damaging chemotherapy.

MSH6 and PMS2 mutation positive Australian Lynch syndrome families: Novel mutations, cancer risk and age of diagnosis of colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 21-05-2010

DOI: 10.1186/1897-4287-8-5

Early changes of endometrial neoplasia revealed by loss of mismatch repair gene protein expression in a patient diagnosed with Lynch syndrome

Publisher: Elsevier BV

Date: 2016

DOI: 10.1016/J.PATHOL.2015.11.003

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 21-01-2009

DOI: 10.1038/EJHG.2008.239

Genetic testing: A round table conversation [4] (multiple letters)

Publisher: Wiley

Date: 09-2004

DOI: 10.1111/J.1445-5994.2004.00679.X

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Publisher: Springer Science and Business Media LLC

Date: 14-01-2019

DOI: 10.1038/S41588-018-0309-3

Parental smoking and risk of childhood brain tumors

Publisher: Wiley

Date: 13-02-2013

DOI: 10.1002/IJC.28004

Abstract: Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. Tobacco smoke contains 61 known carcinogens and increases the risk of several adult cancers. This study investigated associations between parental smoking and risk of CBT in a population-based case-control study conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, controls via nationwide random-digit dialing, frequency matched to cases on age, sex and state of residence. Parental smoking information was obtained for 302 cases and 941 controls through mailed questionnaires that requested average daily cigarette use in each calendar year from age 15 to the child's birth, linked to residential and occupational histories. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders. Overall, parental smoking before or during pregnancy showed no association with CBT risk. The odds ratios for maternal smoking before and during pregnancy were 0.99 (95% CI: 0.70, 1.40) and 0.89 (95% CI: 0.61, 1.21), respectively, and those for paternal smoking before and during pregnancy were 0.99 (95% CI: 0.71, 1.38) and 1.04 (95% CI: 0.74, 1.46), respectively. In children under 24 months of age, the odds ratios for maternal smoking preconception and during pregnancy were 5.06 (95% CI 1.35-19.00) and 4.61 (95% CI: 1.08, 19.63), although these results were based on modest numbers. Future studies should investigate the associations between maternal smoking and risk of CBT by the child's age of diagnosis.

Influence of the Levels of Arsenic, Cadmium, Mercury and Lead on Overall Survival in Lung Cancer

Publisher: MDPI AG

Date: 05-08-2021

DOI: 10.3390/BIOM11081160

Abstract: The effects of heavy metals on cancer risk have been widely studied in recent decades, but there is limited data on the effects of these elements on cancer survival. In this research, we examined whether blood concentrations of the heavy metals arsenic, cadmium, mercury and lead were associated with the overall survival of lung cancer patients. The study group consisted of 336 patients with lung cancer who were prospectively observed. Blood concentrations of heavy metals were measured to study the relationship between their levels and overall survival using Cox proportional hazards analysis. The hazard ratio of death from all causes was 0.99 (p = 0.94) for arsenic, 1.37 (p = 0.15) for cadmium, 1.55 (p = 0.04) for mercury, and 1.18 (p = 0.47) for lead in patients from the lowest concentration quartile, compared with those in the highest quartile. Among the patients with stage IA disease, this relationship was statistically significant (HR = 7.36 p 0.01) for cadmium levels in the highest quartile ( .97–7.77 µg/L) compared to quartile I (0.23–0.57 µg/L, reference). This study revealed that low blood cadmium levels .47 µg/L are probably associated with improved overall survival in treated patients with stage IA disease.

Xeroderma pigmentosum genes and melanoma risk

Publisher: Wiley

Date: 13-03-2013

DOI: 10.1002/IJC.28123

Abstract: Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15 p < 0.001) and the rs2228000_TT genotype (OR = 0.11 p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26 p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility.

The PAI-1 4G/5G Gene Polymorphism and Ischemic Stroke: An Association Study and Meta-Analysis

Publisher: Elsevier BV

Date: 07-2007

DOI: 10.1016/J.JSTROKECEREBROVASDIS.2007.03.002

Abstract: To investigate whether the 4G/5G polymorphism of plasminogen activator inhibitor type 1 (PAI-1) and the -7351 C/T polymorphism of tissue-type plasminogen activator (t-PA) are associated with ischemic stroke, we conducted a case-control study of 190 hospital cases of first-ever ischemic stroke and 185 community-based controls. Our findings do not indicate any association between the PAI-1 or t-PA polymorphisms and risk of stroke. Adding our PAI-1 results to previous studies in a meta-analysis indicated a strong association between this polymorphism and ischemic stroke (P = .0002), with no publication bias but with extreme heterogeneity. There was evidence of stroke association with the PAI-1 4G/5G locus. Strong heterogeneity indicates the need to address other issues, including association with particular stroke subtypes or linkage disequilibrium (LD) with another causative allele. The results also sound a cautionary note that varying LD structure across populations may obscure the relationship with a causative locus, and that future meta-analyses need to look beyond a simple pooled estimate.

Erratum to: Exposure to pesticides and the risk of childhood brain tumors

Publisher: Springer Science and Business Media LLC

Date: 07-2014

DOI: 10.1007/S10552-014-0418-Y

Characterization of the early molecular changes in the glomeruli of Cd151 −/− mice highlights induction of mindin and MMP-10

Publisher: Springer Science and Business Media LLC

Date: 22-11-2017

DOI: 10.1038/S41598-017-15993-3

Abstract: In humans and FVB/N mice, loss of functional tetraspanin CD151 is associated with glomerular disease characterised by early onset proteinuria and ultrastructural thickening and splitting of the glomerular basement membrane (GBM). To gain insight into the molecular mechanisms associated with disease development, we characterised the glomerular gene expression profile at an early stage of disease progression in FVB/N Cd151 −/− mice compared to Cd151 +/+ controls. This study identified 72 up-regulated and 183 down-regulated genes in FVB/N Cd151 −/− compared to Cd151 +/+ glomeruli (p 0.05). Further analysis highlighted induction of the matrix metalloprotease MMP-10 and the extracellular matrix protein mindin (encoded by Spon2 ) in the diseased FVB/N Cd151 −/− GBM that did not occur in the C57BL/6 diseased-resistant strain. Interestingly, mindin was also detected in urinary s les of FVB/N Cd151 −/− mice, underlining its potential value as a biomarker for glomerular diseases associated with GBM alterations. Gene set enrichment and pathway analysis of the microarray dataset showed enrichment in axon guidance and actin cytoskeleton signalling pathways as well as activation of inflammatory pathways. Given the known function of mindin, its early expression in the diseased GBM could represent a trigger of both further podocyte cytoskeletal changes and inflammation, thereby playing a key role in the mechanisms of disease progression.

Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

Publisher: Cold Spring Harbor Laboratory

Date: 19-06-2020

DOI: 10.1101/2020.06.16.146803

Abstract: We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective s le size: 237,483 cases/317,006 controls). This identified 465 independent lead variants ( P ×10 −8 ) across 192 genomic regions. Four lead variants were Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes ( P .6×10 −6 ) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.

Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation

Publisher: Elsevier BV

Date: 02-2008

DOI: 10.1016/J.AJHG.2007.11.002

Prognostic implications of cancer susceptibility genes: any news?

Publisher: Springer Berlin Heidelberg

Date: 1999

DOI: 10.1007/978-3-642-59945-3_5

Abstract: Recent advances in our understanding of the genetic basis of several inherited predispositions to cancer have raised the possibility that there may be differences in prognosis between patients harbouring genetic susceptibilities to cancer and persons presenting with sporadic disease. The two best studied models of inherited susceptibilities to cancer will be considered, those of colorectal cancer and familial breast cancer. Familial colorectal cancer can be sub ided into essentially two groups: familial adenomatous polyposis and hereditary non-polyposis colorectal cancer. Familial breast cancer can be sub ided into three groups: those that can be accounted for by mutations in the breast cancer susceptibility gene BRCA 1, families harbouring mutations in BRCA 2 and families where neither BRCA 1 nor BRCA 2 appear to be involved. In this chapter several aspects of these inherited cancer predispositions will be discussed and compared with their equivalent sporadic disease counterparts.

Founder Mutations for Early Onset Melanoma as Revealed by Whole Exome Sequencing Suggests That This is Not Associated with the Increasing Incidence of Melanoma in Poland

Publisher: Korean Cancer Association

Date: 15-01-2019

DOI: 10.4143/CRT.2018.157

Planning the Human Variome Project: The Spain report

Publisher: Hindawi Limited

Date: 20-01-2009

DOI: 10.1002/HUMU.20972

Survival of bladder or renal cancer in patients with CHEK2 mutations

Publisher: Public Library of Science (PLoS)

Date: 09-09-2021

DOI: 10.1371/JOURNAL.PONE.0257132

Abstract: The purpose of this study was to compare the clinical characteristics and the survival of CHEK2 mutation positive and CHEK2 mutation negative patients diagnosed with bladder or kidney cancer. 1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four CHEK2 variants: 1100delC, del5395, IVS2+1G A and I157T. Predictors of survival were determined among CHEK2 pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (≤60 years), sex (female male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking smoking) and cancer family history (negative positive). We found no impact of CHEK2 mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with CHEK2 mutations but this did not meet statistical significance (HR = 0.14 95% CI 0.02–1.04 p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9 95% CI 1.50–42.1 p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4 95% CI 1.30–4.55 p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12 95% CI 0.02–0.66 p = 0.04) and those with stage T1 disease (OR = 0.2 95% CI 0.07–0.76 p = 0.01). Our investigations revealed that any mutation in CHEK2 occurs more often among patients with stage Ta bladder cancer (OR = 2.0 95% CI 1.19–3.47 p = 0.01) and less often in patients with stage T1 disease (OR = 0.31 95% CI 0.12–0.78 p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0 95% CI 0.95–67.7 p = 0.05). The 10-year survival for all CHEK2 mutation carriers with bladder cancer was 33% and for non-carriers 11% ( p = 0.15). The 10-year survival for CHEK2 mutation carriers with kidney cancer 34% and for non-carriers 20% ( p = 0.5). CHEK2 mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of CHEK2 mutations on survival for patients with stage T1 bladder cancer. CHEK2 missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T CHEK2 pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in CHEK2 was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating CHEK2 mutations were associated with kidney cancer patients with GII clear cell carcinoma.

Continuing difficulties in interpreting CNV data: Lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

Publisher: Springer Science and Business Media LLC

Date: 26-03-2013

DOI: 10.1186/1755-8794-6-10

Ischemic stroke is associated with the ABO locus: The EuroCLOT study

Publisher: Wiley

Date: 2013

DOI: 10.1002/ANA.23838

Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the β6 integrin subunit

Publisher: Wiley

Date: 08-04-2002

DOI: 10.1002/IJC.10397

Abstract: We have previously reported that the alphavbeta6 integrin upregulates its own expression in a protein kinase C-dependent manner with increasing cell density. The wild-type beta6 integrin subunit has also been shown to promote tumour growth in vivo and its growth-enhancing effect is regulated by both a MAP kinase binding motif on beta6 and the 11 amino acid C-terminal cytoplasmic extension unique to the beta6 subunit. Herein, we show that the 11 amino acid cytoplasmic extension is essential for the cell density-dependent increase in beta6 expression and that the 11 amino acid tail exerts a dominant negative effect on cell density- and PKC-mediated beta5 expression in alphavbeta6-expressing colon cancer cells. Cells that express beta6 lacking the 11 amino acid tail respond to PKC simulation with increased expression of only the beta5 subunit as seen for cells that lack constitutive alphavbeta6 expression. In contrast, loss of the ERK binding site on beta6 markedly impairs cell density- and PKC-dependent expression of either beta6 or beta5 in the presence or absence of the 11 amino acid tail, respectively. Our findings suggest that in alphavbeta6-expressing cells, a hierarchy of kinase signalling cascades exists and that the beta6-ERK2 interaction dominates over PKC-mediated signalling pathways responsible for integrin upregulation with cell confluence. Given the dominance of the beta6-ERK2 interaction over PKC-mediated expression of both beta5 and beta6 integrin subunits, targeting the beta6-ERK2 interaction may prove useful as an anticancer strategy in colon cancer.

Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.PATHOL.2017.05.004

Abstract: Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied.

Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2001

DOI: 10.1007/BF02234627

Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1016/J.JPSYCHIRES.2013.10.018

Abstract: The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val(158)Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val(158)Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers.

Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.AJHG.2018.03.021

Exposure to professional pest control treatments and the risk of childhood acute lymphoblastic leukemia

Publisher: Wiley

Date: 11-02-2011

DOI: 10.1002/IJC.25769

Abstract: Previous studies suggest that exposure to pesticides increases the risk of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to investigate whether professional pest treatments in or around the home before birth or during childhood increased the risk of childhood ALL. Data from 388 cases and 870 frequency-matched controls were analyzed using unconditional logistic regression, adjusting for study matching variables and potential confounders, to calculate odds ratios (ORs). A meta-analysis of our findings with the published findings of previous studies was also conducted. The ORs for any professional pest control treatments were 1.19 (95% CI 0.83, 1.69) in the year before pregnancy, 1.30 (95% CI 0.86, 1.97) during pregnancy and 1.24 (95% CI 0.93, 1.65) for those done after the child's birth. The ORs for exposure after birth were highest when it occurred between the ages of two and three years. ORs were elevated for termite treatments before birth. ORs were higher for pre-B than T cell ALL and for t(12 ) (ETV6-Runx-1) than other cytogenetic sub-types. The pooled OR from a meta-analysis of our study with three previous studies of professional pest control treatments during pregnancy was 1.37 (95% CI 1.00, 1.88). Our results, and those of our meta-analysis, provide some evidence of a modestly increased risk of ALL for professional pest control treatments done during the index pregnancy and possibly in the child's early years. The analysis of pooled data from international collaborations may provide more certainty regarding these potentially important associations.

LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Publisher: Springer Science and Business Media LLC

Date: 02-02-2015

DOI: 10.1038/NG.3211

Blood cadmium levels as a marker for early lung cancer detection

Publisher: Elsevier BV

Date: 03-2021

DOI: 10.1016/J.JTEMB.2020.126682

Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families

Publisher: Springer Science and Business Media LLC

Date: 16-01-2015

DOI: 10.1186/S13053-015-0025-2

Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma

Publisher: American Thoracic Society

Date: 09-2005

DOI: 10.1164/RCCM.200503-369OC

The genetic architecture of the human cerebral cortex

Publisher: Cold Spring Harbor Laboratory

Date: 03-09-2018

DOI: 10.1101/399402

Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 in iduals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci ( P ≤ 5 × 10 −8 ) 199 survived multiple testing correction ( P ≤ 8.3 × 10 −10 187 surface area 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression and ADHD. Common genetic variation is associated with inter-in idual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.

Haplotype and Phenotype Analysis of Nine Recurrent BRCA2 Mutations in 111 Families: Results of an International Study

Publisher: Elsevier BV

Date: 06-1998

DOI: 10.1086/301885

Genetically Determined Risk of Depression and Functional Outcome After Ischemic Stroke.

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-2019

DOI: 10.1161/STROKEAHA.119.026089

Abstract: Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81 95% CI, 0.98–3.35 P =0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P =0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57 95% CI, 1.05–6.25 P =0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81 95% CI, 0.95–3.46 P =0.08). We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.

Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status

Publisher: BMJ

Date: 11-1998

DOI: 10.1136/GUT.43.5.675

Abstract: Background —Familial adenomatous polyposis (FAP) is a clinically well defined hereditary disease caused by germline mutations within the adenomatous polyposis coli (APC) gene. Although several techniques are applied in the mutation analysis of FAP kindreds about 20–50% of cases remain unclear, with no APC mutation identified (APC negative). Aims —To delineate phenotypic differences between APC positive and APC negative patients with respect to colonic and extracolonic disease in order to determine whether additional mechanisms are involved in the pathogenesis of FAP. Methods —The entire coding region of the APC gene was analysed using single stranded conformation polymorphism and protein truncation tests in 50 Swiss FAP families with a total of 161 affected in iduals. Differences in phenotypic manifestation were statistically evaluated by Student’s t test, Fisher’s exact test, and χ 2 test. Results —Thirty six families (72%) were APC positive. Statistically significant differences between APC positive and APC negative groups were found for the mean age at diagnosis of colonic polyposis (35.2 versus 45.3 years, respectively) and for the occurrence of stomach polyps (14 patients, all APC positive). Additionally, APC negative patients displayed lower polyp numbers at diagnosis and less extracolonic manifestations. Conclusions— FAP kindreds without detected APC gene mutations present with a notably milder disease phenotype compared with APC positive families, suggesting that different genetic factors might be involved.

DNA mismatch repair genes and hereditary non-polyposis colorectal cancer

Publisher: Wiley

Date: 10-03-2004

DOI: 10.1111/J.1440-1746.2004.03425.X

Direct integrin αvβ6-ERK binding: implications for tumour growth

Publisher: Springer Science and Business Media LLC

Date: 21-02-2002

DOI: 10.1038/SJ.ONC.1205286

Abstract: Blockade of the mitogen-activated protein (MAP) kinase pathway suppresses growth of colon cancer in vivo. Here we demonstrate a direct link between the extracellular signal-regulated kinase ERK2 and the growth-promoting cell adhesion molecule, integrin alphavbeta6, in colon cancer cells. Down-regulation of beta6 integrin subunit expression inhibits tumour growth in vivo and MAP kinase activity in response to serum stimulation. In alphavbeta6-expressing cells ERK2 is bound only to the beta6 subunit. The increase in cytosolic MAP kinase activity upon epidermal growth factor stimulation is all accounted for by beta6-bound ERK. Deletion of the ERK2 binding site on the beta6 cytoplasmic domain inhibits tumour growth and leads to an association between ERK and the beta5 subunit. The physical interaction between integrin alphavbeta6 and ERK2 defines a novel paradigm of integrin-mediated signalling and provides a therapeutic target for cancer treatment.

Germline 657del5 mutation in the NBS1 gene in breast cancer patients

Publisher: Wiley

Date: 16-05-2003

DOI: 10.1002/IJC.11231

Abstract: In this report the proportion of consecutive and familial breast cancer cases harboring the 657del5 of exon 6 of the NBS1 gene was determined to assess whether it is associated with the increased risk of breast cancer development. The study consisted of 3 groups of patients: a series of consecutive 150 patients with histologically confirmed breast cancer, diagnosed under the age of 50 in the city of Szczecin a series of 80 breast cancer patients with a family history of breast cancer in their first-degree relatives and a series of 530 consecutive in iduals without the diagnosis of breast cancer selected at random by family doctors from the city of Szczecin. Molecular examination included allele-specific PCR assay for the common Slavic NBS1 mutation (657del5), LOH analysis using denucleotide CA repeat microsatellite markers, haplotype analysis and sequencing. The NBS1 founder mutation was detected in 2 of 150 (1.3%) consecutive breast cancer cases diagnosed under the age of 50 years in 3 of 80 familial breast cancer cases (3.7%) and in 3 of 530 in iduals (0.6%) from the general population. Examination of tumor DNA from patients with the NBS1 mutation (groups A and B) revealed loss of heterozygosity (LOH) in all cases. Additional haplotype analysis revealed that allelic loss affects specifically wild-type alleles. The majority of probands with breast cancer and the NBS1 mutation had a positive family history of breast cancer in their first-degree relatives. It appears that the 657del5 mutation in exon 6 of the NBS1 gene is responsible for the occurrence of a small but significant proportion of familial breast cancer patients.

Genome-wide miRNA, gene and methylation analysis of triple negative breast cancer to identify changes associated with lymph node metastases

Publisher: Elsevier BV

Date: 12-2017

DOI: 10.1016/J.GDATA.2017.07.004

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

Publisher: Springer Science and Business Media LLC

Date: 31-05-2021

DOI: 10.1038/S41598-021-90501-2

Abstract: In iduals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1 , MSH2 or MSH6, for rs2075786 (G A, intronic variant), 1207 LS patients for rs2736108 (C T, upstream variant) and 1201 LS patients for rs7705526 (C A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of s le origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers ( p = 0.0160). Kaplan–Meier analysis also shows an association for rs2075786 the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.

Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.SCHRES.2016.07.006

Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age

Publisher: Wiley

Date: 16-03-2009

DOI: 10.1002/IJC.24304

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 in iduals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian s le only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.

Cytokine gene polymorphism among Indigenous Australians

Publisher: SAGE Publications

Date: 12-08-2014

DOI: 10.1177/1753425913498911

Abstract: The health profile of Indigenous Australians is characterised by high rates of classic ‘lifestyle’ diseases. Potential roles of inflammation in pathophysiology of these diseases requires investigation. It is not clear if genetic regulation of inflammation in Indigenous Australians is similar to other populations. This study characterised frequencies of single nucleotide polymorphisms (SNPs) for eight cytokine genes for 100 in iduals from a remote Indigenous Australian community and assessed novel genetic variants in four cytokine genes. We used a commercially-available allelic discrimination assay for SNP genotyping re-sequencing was undertaken by standard Sanger sequencing methodologies for 26 s les. Frequencies of cytokine gene SNPs differed significantly from the Caucasian population ( P 0.001−0.044). Twenty-five novel variants were identified across four re-sequenced genes frequencies ranged from % to 100%. Genotype frequencies observed in Indigenous Australians did not consistently resemble reported HapMap frequencies in Northern and Western European populations, Yoruba Nigerian or Han Chinese. Our findings indicate Indigenous Australians might have an inherited propensity for strong inflammatory responses. Preliminary evidence of novel genetic variants highlights the need to catalogue the extent of genetic variation in specific population groups. Improved understanding of differences in genetic variation between specific population groups could assist in assessment of risk for lifestyle diseases.

Five endometrial cancer risk loci identified through genome-wide association analysis

Publisher: Springer Science and Business Media LLC

Date: 02-05-2016

DOI: 10.1038/NG.3562

Whole genome amplification and its impact on CGH array profiles

Publisher: Springer Science and Business Media LLC

Date: 29-07-2008

DOI: 10.1186/1756-0500-1-56

Abstract: Some array comparative genomic hybridisation (array CGH) platforms require a minimum of micrograms of DNA for the generation of reliable and reproducible data. For studies where there are limited amounts of genetic material, whole genome lification (WGA) is an attractive method for generating sufficient quantities of genomic material from miniscule amounts of starting material. A range of WGA methods are available and the multiple displacement lification (MDA) approach has been shown to be highly accurate, although lification bias has been reported. In the current study, WGA was used to lify DNA extracted from whole blood. In total, six array CGH experiments were performed to investigate whether the use of whole genome lified DNA (wgaDNA) produces reliable and reproducible results. Four experiments were conducted on lified DNA compared to un lified DNA and two experiments on un lified DNA compared to un lified DNA. All the experiments involving wgaDNA resulted in a high proportion of losses and gains of genomic material. Previously, lification bias has been overcome by using lified DNA in both the test and reference DNA. Our data suggests that this approach may not be effective, as the gains and losses introduced by WGA appears to be random and are not reproducible between different experiments using the same DNA. In light of these findings, the use of both lified test and reference DNA on CGH arrays may not provide an accurate representation of copy number variation in the DNA.

Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpolyposis colorectal cancer patients

Publisher: American Association for Cancer Research (AACR)

Date: 11-2006

DOI: 10.1158/1055-9965.EPI-06-0040

Abstract: Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germ-line mutations in DNA mismatch repair genes. There is considerable variation in disease expression that cannot be explained by genotype henotype correlation, which is likely to be the result of polymorphic modifier genes. One candidate group of modifiers is the xenobiotic clearance enzyme genes that encode CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. Alterations in these xenobiotic clearance genes can potentially influence the host response to carcinogen exposure and thereby alter cancer risk. We have investigated eight polymorphisms in xenobiotic clearance genes to assess the effect on the risk of disease in mutation positive HNPCC patients. Methods: DNA s les from 220 mutation-positive HNPCC participants (86 Australian and 134 Polish) were genotyped for single nucleotide polymorphisms (SNP) in CYP1A1, GSTM1, GSTT1, GSTP1, and NAT2. The association between the SNPs and disease characteristics, disease expression and age of diagnosis of colorectal cancer (CRC), was tested with Pearson's χ2 and Kaplan-Meier survival analysis. Results: The HNPCC population displays a significant difference in the genotype frequency distribution between CRC patients and unaffected mismatch repair gene mutation carriers for the CYP1A1 SNP where the CRC patients harbor more of the mutant genotype. Conclusions: Evidence from this study is not conclusive, but our data suggest that the CYP1A1 influences disease expression in in iduals with HNPCC. (Cancer Epidemiol Biomarkers Prev 2006 (11):2307–10)

The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells

Publisher: Oxford University Press (OUP)

Date: 08-04-2031

DOI: 10.1093/HMG/DDT529

Abstract: Genome-wide association studies have identified a linkage disequilibrium (LD) block on chromosome 12 associated with multiple sclerosis (MS), type 1 diabetes and other autoimmune diseases. This block contains CYP27B1, which catalyzes the conversion of 25 vitamin D3 (VitD3) to 1,25VitD3. Fine-mapping analysis has failed to identify which of the 17 genes in this block is most associated with MS. We have previously used a functional approach to identify the causal gene. We showed that the expression of several genes in this block in whole blood is highly associated with the MS risk allele, but not CYP27B1. Here, we show that CYP27B1 is predominantly expressed in dendritic cells (DCs). Its expression in these cells is necessary for their response to VitD, which is known to upregulate pathways involved in generating a tolerogenic DC phenotype. Here, we utilize a differentiation protocol to generate inflammatory (DC1) and tolerogenic (DC2) DCs, and show that for the MS risk allele CYP27B1 is underexpressed in DCs, especially DC2s. Of the other Chr12 LD block genes expressed in these cells, only METT21B expression was as affected by the genotype. Another gene associated with autoimmune diseases, CYP24A1, catabolizes 1,25 VitD3, and is predominantly expressed in DCs, but equally between DC1s and DC2s. Overall, these data are consistent with the hypothesis that reduced VitD pathway gene upregulation in DC2s of carriers of the risk haplotype of CYP27B1 contributes to autoimmune diseases. These data support therapeutic approaches aimed at targeting VitD effects on DCs.

Cell cycle dependent DNA break increase in ataxia telangiectasia lymphoblasts after radiation exposure

Publisher: BMJ

Date: 10-2001

DOI: 10.1136/MP.54.5.347

Abstract: The most striking feature of ataxia telangiectasia (AT) cells is their profound sensitivity to ionising radiation. A deficiency in the rejoining of radiation induced DNA breaks has been suggested to be responsible for AT radiosensitivity however, the existing literature is controversial. A subpopulation, which is present in irradiated AT lymphoblasts, but rarely in controls, has been reported previously. The cells that make up this subpopulation harbour highly fragmented DNA and are responsible for the overall increase in DNA breaks soon after irradiation in AT lymphoblasts. This study examines the influence of the cell cycle on the highly damaged subpopulation. The frequency of highly damaged cells was highest when AT lymphoblasts were irradiated during the G2/M phase. In contrast, AT lymphoblasts irradiated during the G0/G1 phase displayed a frequency similar to control cells. Thus, only G2/M and to some extent S phase cells contribute to an increased DNA break number in AT lymphoblasts early after irradiation. These findings might explain several inconsistencies reported in the literature.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Publisher: Springer Science and Business Media LLC

Date: 09-12-2022

DOI: 10.1038/S41380-022-01897-W

Abstract: Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years range 18–72 years 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was in idually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19 I 2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation

Publisher: Public Library of Science (PLoS)

Date: 04-08-2011

DOI: 10.1371/JOURNAL.PONE.0023127

KRAS mutation testing of metastatic colorectal cancer in Australia: Where are we at?

Publisher: Wiley

Date: 09-05-2014

DOI: 10.1111/AJCO.12201

Abstract: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutation frequencies and turnaround times that might impact on patient care. Participating laboratories contributed information on KRAS mutation frequencies, including the G13D mutation type, as well as turnaround times for tumor block retrieval and testing. The KRAS mutation frequency observed by nine different test sites for a total of 3688 metastatic colorectal cancers ranged from 34.4% to 40.7%, with an average across all sites of 38.8%. The average frequency of the G13D mutation type among all cases was 8.0%. The median turnaround time was 17 days (range 0-191), with 20% of cases requiring more than 4 weeks for a KRAS test result. The major contributor to long turnaround times was the time taken to retrieve archived blocks of primary tumor, particularly from sources external to the test site. The frequency of KRAS mutations in metastatic colorectal cancer reported by the major Australian test sites is very similar to that reported by other large overseas studies. More widespread introduction of routine testing at the time of initial diagnosis should eliminate the long turnaround times currently being experienced in a significant proportion of cases. Future expansion of testing to include other KRAS and NRAS mutation hotspots may spur the introduction of next-generation sequencing platforms.

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2023

DOI: 10.1161/STROKEAHA.122.040715

Abstract: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ] P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98] P =0.0041). The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 31-10-2016

DOI: 10.1158/1055-9965.EPI-16-0147

Abstract: Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) in idual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22 95% CI, 1.10–1.39 P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P & 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with in idual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev 25(11) 1503–10. ©2016 AACR.

The MinION as a cost-effective technology for diagnostic screening of the SCN1A gene in epilepsy patients

Publisher: Elsevier BV

Date: 05-2021

DOI: 10.1016/J.EPLEPSYRES.2021.106593

Paracingulate sulcus morphology is associated with hallucinations in the human brain

Publisher: Springer Science and Business Media LLC

Date: 17-11-2015

DOI: 10.1038/NCOMMS9956

Abstract: Hallucinations are common in psychiatric disorders, and are also experienced by many in iduals who are not mentally ill. Here, in 153 participants, we investigate brain structural markers that predict the occurrence of hallucinations by comparing patients with schizophrenia who have experienced hallucinations against patients who have not, matched on a number of demographic and clinical variables. Using both newly validated visual classification techniques and automated, data-driven methods, hallucinations were associated with specific brain morphology differences in the paracingulate sulcus, a fold in the medial prefrontal cortex, with a 1 cm reduction in sulcal length increasing the likelihood of hallucinations by 19.9%, regardless of the sensory modality in which they were experienced. The findings suggest a specific morphological basis for a pervasive feature of typical and atypical human experience.

Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+ T cells

Publisher: Springer Science and Business Media LLC

Date: 27-08-2016

DOI: 10.1186/S13148-016-0253-Y

Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

Publisher: American Association for Cancer Research (AACR)

Date: 06-2012

DOI: 10.1158/1055-9965.EPI-11-1160

Abstract: Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P & 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all s les). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5). Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev 21(6) 980–7. ©2012 AACR.

Regulators of Global Genome Repair Do Not Respond to DNA Damaging Therapy but Correlate with Survival in Melanoma

Publisher: Public Library of Science (PLoS)

Date: 05-08-2013

DOI: 10.1371/JOURNAL.PONE.0070424

STaRRRT: A table of short tandem repeats in regulatory regions of the human genome

Publisher: Springer Science and Business Media LLC

Date: 15-11-2013

DOI: 10.1186/1471-2164-14-795

Abstract: Tandem repeats (TRs) are unstable regions commonly found within genomes that have consequences for evolution and disease. In humans, polymorphic TRs are known to cause neurodegenerative and neuromuscular disorders as well as being associated with complex diseases such as diabetes and cancer. If present in upstream regulatory regions, TRs can modify chromatin structure and affect transcription resulting in altered gene expression and protein abundance. The most common TRs are short tandem repeats (STRs), or microsatellites. Promoter located STRs are considerably more polymorphic than coding region STRs. As such, they may be a common driver of phenotypic variation. To study STRs located in regulatory regions, we have performed genome-wide analysis to identify all STRs present in a region that is 2 kilobases upstream and 1 kilobase downstream of the transcription start sites of genes. The Short Tandem Repeats in Regulatory Regions Table, STaRRRT, contains the results of the genome-wide analysis, outlining the characteristics of 5,264 STRs present in the upstream regulatory region of 4,441 human genes. Gene set enrichment analysis has revealed significant enrichment for STRs in cellular, transcriptional and neurological system gene promoters and genes important in ion and calcium homeostasis. The set of enriched terms has broad similarity to that seen in coding regions, suggesting that regulatory region STRs are subject to similar evolutionary pressures as STRs in coding regions and may, like coding region STRs, have an important role in controlling gene expression. STaRRRT is a readily-searchable resource for investigating potentially polymorphic STRs that could influence the expression of any gene of interest. The processes and genes enriched for regulatory region STRs provide potential novel targets for diagnosing and treating disease, and support a role for these STRs in the evolution of the human genome.

Colorectal carcinoma in the course of inflammatory bowel diseases

Publisher: Springer Science and Business Media LLC

Date: 12-07-2019

DOI: 10.1186/S13053-019-0118-4

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Publisher: Springer Science and Business Media LLC

Date: 18-04-2016

DOI: 10.1038/NG.3552

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

Publisher: S. Karger AG

Date: 2018

DOI: 10.1159/000484532

Abstract: The overgrowth syndromes are important to diagnose, not just for accurate genetic counseling, but also for knowledge surrounding cancer surveillance and prognosis. There has been a recent expansion in the number of genes associated with a mendelian overgrowth phenotype, so this review updates previous classifications of overgrowth syndromes. We also describe a clinical and molecular approach to the investigation of in iduals presenting with overgrowth. This review aims to assist the clinical diagnosis of generalized overgrowth syndromes by outlining the salient features of well-known overgrowth syndromes alongside the many syndromes that have been discovered and classified more recently. We provide key clinical “handles” to aid clinical diagnosis and a list of genes to aid with panel design when using next generation sequencing, which we believe is frequently needed due to the overlapping phenotypic features seen between overgrowth syndromes.

Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT

Publisher: Oxford University Press (OUP)

Date: 09-2008

DOI: 10.1111/J.1365-2133.2008.08827.X

Abstract: The receptor tyrosine kinase c-KIT plays a key role in normal mast cell development. Point mutations in c-KIT have been associated with sporadic or familial mastocytosis. Two unrelated pairs of apparently identical twins affected by cutaneous mastocytosis attending the Mastocytosis Clinic at the Royal Children's Hospital, Melbourne, provided an opportunity to assess the possible contribution of c-KIT germline mutations or polymorphisms in this disease. Tissue biopsy, blood and/or buccal swab specimens were collected from 10 children with mastocytosis. To detect germline mutations olymorphisms in c-KIT, we studied all coding exons by denaturing high pressure liquid chromatography. Exons showing mismatches were examined by direct sequencing. The influence of the substitution identified was further examined by expressing the variant form of c-KIT in factor-dependent FDC-P1 cells. In both pairs of twins, a heterozygous ATG to CTG transition in codon 541 was observed, resulting in the substitution of a methionine residue in the transmembrane domain by leucine (M541L). In each case, one parent was also heterozygous for this allele. Expression of M541L KIT in FDC-P1 cells enabled them to grow in human KIT ligand (stem cell factor, SCF) but did not confer factor independence. Compared with cells expressing wild-type KIT at a similar level, M541L KIT-expressing cells displayed enhanced growth at low levels of SCF, and heightened sensitivity to the KIT inhibitor, imatinib mesylate. The data suggest that the single nucleotide polymorphism resulting in the substitution M541L may predispose to paediatric mastocytosis.

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations

Publisher: Oxford University Press (OUP)

Date: 05-08-1998

DOI: 10.1093/JNCI/90.15.1138

Abstract: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in in iduals with a family history of the disease and may ultimately aid in the clinical management of patients.

CYP1B1 and predisposition to breast cancer in Poland

Publisher: Springer Science and Business Media LLC

Date: 26-04-2007

DOI: 10.1007/S10549-007-9500-4

Abstract: The CYP1B1 gene is a polymorphic member of the P450 gene family and is considered to be a candidate gene for cancers of various types. We inquired whether four SNPs in the CYP1B1 gene, alone or in combination, might be associated with breast cancer risk in Poland. We genotyped 2017 cases of breast cancer and 876 controls, for four SNPs in the CYP1B1 gene. Genotype and haplotype frequencies were compared in cases and controls. In combinations of the R48G, A119S and L432V SNPs, four of the eight CYP1B1 haplotypes were more common in controls than in cases and each of these appeared to have a significant protective effect. A large reduction in risk was observed for women who were homozygous for one of these four haplotypes (OR = 0.2 95% CI = 0.05-0.5 P = 0.001) compared to women who were homozygous for the most common haplotype. In contrast, women who were homozygous for the GTC haplotype were at increased risk (OR = 1.5 95% CI = 1.0-2.1 P = 0.03) compared to women with the most common haplotype. The CYP1B1 gene appears to influence breast cancer susceptibility in Poland.

Genome-wide association study identifies 74 loci associated with educational attainment.

Publisher: Springer Science and Business Media LLC

Date: 11-05-2016

DOI: 10.1038/NATURE17671

Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis

Publisher: MDPI AG

Date: 22-10-2012

DOI: 10.3390/IJMS131013667

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (−597 G A and −174 G C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (−572 G C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different −597 or −174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of in iduals with MS who carried a C allele at position −572, although this was not significant after correction for multiple comparisons. Interestingly, however, the −572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression.

Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Publisher: Cold Spring Harbor Laboratory

Date: 02-05-2020

DOI: 10.1101/2020.04.29.20084095

Abstract: Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For ex le, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 −5 ). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (P Bonferroni 2.4 × 10 −9 ). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P 5 × 10 −7 ). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer

Publisher: Springer Science and Business Media LLC

Date: 17-01-2022

DOI: 10.1038/S41523-021-00373-Y

Abstract: While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF 0.001, OR 1.57, 95% CI 1.00–2.44, p = 0.05), particularly for variants with a REVEL score .5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with biallelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten that remained heterozygous. Biallelic loss of the wild-type alleles corresponded strongly with ER- and TN breast tumours, high homologous recombination deficiency scores and mutational signature 3. Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case–control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls and seven out of eight tumours showing no biallelic inactivation or characteristic mutational signature. Conversely, evaluation of case–control findings and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.

Time‐resolved proteomic profiling of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

Publisher: Wiley

Date: 05-07-2021

DOI: 10.1111/RESP.14111

Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. We employed quantitative label‐based proteomics to map the changes in the lung tissue proteome of cigarette smoke‐induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4‐ and 6‐week time points, compared to age‐matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy s les. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA‐binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.

Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis

Publisher: Public Library of Science (PLoS)

Date: 05-03-2013

DOI: 10.1371/JOURNAL.PONE.0056379

Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis

Publisher: Springer Science and Business Media LLC

Date: 02-07-2015

DOI: 10.1186/S12916-015-0392-6

Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

Publisher: Wiley

Date: 18-04-2016

DOI: 10.1002/IJC.30116

Abstract: Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.

The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Publisher: Public Library of Science (PLoS)

Date: 11-06-2015

DOI: 10.1371/JOURNAL.PONE.0127080

Homologous recombination DNA repair defects in PALB2-associated breast cancers

Publisher: Springer Science and Business Media LLC

Date: 08-08-2019

DOI: 10.1038/S41523-019-0115-9

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 ( PALB2 ) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2 -associated breast cancers (BCs), and whether PALB2 -associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2 -associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH ( n = 11) or second somatic mutations ( n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2 -associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2 -associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2 -associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Letter to the editor: Blood processing and sample storage have negligible effects on methylation

Publisher: Springer Science and Business Media LLC

Date: 14-02-2018

DOI: 10.1186/S13148-018-0455-6

Germline mutation and large deletion analysis of the CDKN2A and ARF genes in families with multiple melanoma or an aggregation of malignant melanoma and breast cancer

Publisher: Wiley

Date: 15-03-2004

DOI: 10.1002/IJC.20163

Abstract: The CDKN2A/ARF genes have been associated with increased risk of malignant melanoma (MM) in families with multiple members affected by disease and in families characterized by the constellation of breast cancer and MM. The exact contribution of CDKN2A/ARF to disease risk remains poorly characterized, especially in erse populations. In this report, the contribution of CDKN2A/ARF germline mutations and large rearrangements to disease in Polish familial MM (FMM) and aggregations of breast cancer and MM were assessed using a strategy that included genomic sequencing, restriction fragment length polymorphism and multiplex ligation-dependent probe lification. We examined 16 FMM cases (group 1), 44 MM probands with a cancer family aggregation (CFA) that included at least one breast cancer (group 2) and 22 breast cancer probands with CFA and MM (group 3). The results revealed a paucity of mutations in CDKN2A/ARF, suggesting that in the Polish population this gene does not contribute significantly to either FMM or MM within the context of CFA.

Profuse familial adenomatous polyposis with an APC exon 3 mutation

Publisher: Springer Science and Business Media LLC

Date: 2001

DOI: 10.1023/A:1011570523343

Abstract: The attenuated form of familial adenomatous polyposis coli (AAPC) is associated with mutations in the adenomatous polyposis coli (APC) gene which cluster in the 5' region of the gene. It has been proposed that a 'genotype-phenotype boundary' exists at codons 159-163, and mutations that are 5' of this boundary will produce AAPC. Herein we document a three-generation family with an exon 3 mutation well to the 5' side of the proposed boundary, in which two affected in iduals have had, in their 40s, a profuse form of familial adenomatous polyposis coli. We conclude that the codon 159-163 'boundary' is indicative rather than definitive. These two patients also had postoperative intra-abdominal adhesions, severely so in one.

DNA Mismatch Repair and Hereditary Nonpolyposis Colorectal Cancer

Publisher: S. Karger AG

Date: 1997

DOI: 10.1159/000218895

Frequency and nature of hMSH6 germline mutations in Polish patients with colorectal, endometrial and ovarian cancers [1]

Publisher: Wiley

Date: 23-06-2006

DOI: 10.1111/J.1399-0004.2006.00630.X

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Publisher: Springer Science and Business Media LLC

Date: 23-10-2017

DOI: 10.1038/NG.3785

Response to Variability in the clinical phenotype among families with HNPCC: The potential importance of the location of the mutation in the gene by Dr. Prathap Bandipalliam [2]

Publisher: Wiley

Date: 23-03-2007

DOI: 10.1002/IJC.22347

Apoptosis is not involved in the hypersensitivity of fanconi anemia cells to mitomycin C

Publisher: Elsevier BV

Date: 07-1994

DOI: 10.1016/0165-4608(94)90218-6

Abstract: A striking feature of Fanconi anemia (FA) cells is their hypersensitivity towards crosslinking agents such as mitomycin C (MMC). In this study, we have shown that treatment of lymphoblastoid cells with MMC resulted in nuclear fragmentation, chromatin condensation, and DNA degradation, which is characteristic of apoptosis. The level of DNA fragmentation 48 hours after MMC treatment reached approximately 33% in both control and FA cells. In addition, 24 hours after drug addition a decrease in the number of cells in the G2/M phase of the cell cycle was seen. This coincided with the appearance of apoptotic cells in the sub-G1 phase, indicating that once the cells had passed through G2/M, apoptosis occurred. The number of apoptotic cells increased to 60% 96 hours after MMC treatment. The number of apoptotic cells increased to 60% 96 hours after MMC treatment. The onset and level of apoptosis was found to be identical in FA and control cell lines, indicating that the FA defect does not lead to abnormal apoptotic cell death.

BRCA1 sequence analysis in women at high risk for susceptibility mutations: Risk factor analysis and implications for genetic testing

Publisher: American Medical Association (AMA)

Date: 15-10-1997

DOI: 10.1001/JAMA.278.15.1242

A multicenter blinded study to evaluate KRAS mutation testing methodologies in the clinical setting

Publisher: Elsevier BV

Date: 11-2009

DOI: 10.2353/JMOLDX.2009.090057

Complement genes contribute sex-biased vulnerability in diverse disorders

Publisher: Springer Science and Business Media LLC

Date: 11-05-2020

DOI: 10.1038/S41586-020-2277-X

EBV and MS: Major cause, minor contribution or red-herring?

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.MSARD.2017.06.002

Abstract: Multiple Sclerosis (MS) is a chronic neurological disease with genetic and environmental risk factors. Epstein Barr-Virus (EBV) has been closely associated with MS but with a significant amount of conflicting evidence. Some of the evidence for EBV involvement in MS includes: almost 100% of MS patients showing past EBV infection, an association with Infectious Mononucleosis (acute EBV infection), higher titres of EBV antibodies associated with an increased risk of MS development, and an overall altered immune response to EBV found in peripheral blood and the CNS of MS patients. However, evidence for EBV presence in the CSF and T cell responses to EBV in MS have been particularly conflicting. Several hypotheses have been proposed for direct and indirect EBV involvement in MS such as 1) Molecular Mimicry 2) Mistaken Self 3) Bystander Damage and 4) Autoreactive B cells infected with EBV. More recently, an association between EBV and human endogenous retrovirus in MS has been shown, which may provide an alternative pathogenetic target for MS treatment. However, if EBV is not the major contributor to MS and is instead one of several viral or infectious agents able to elicit a similar altered immune response, MS development may be the result of a failure of viral clearance in general. This review aims to evaluate the evidence for the currently discussed theories of EBV involvement in MS pathogenesis.

CD36 – a plausible modifier of disease phenotype in familial adenomatous polyposis

Publisher: Springer Science and Business Media LLC

Date: 28-07-2018

DOI: 10.1186/S13053-018-0096-Y

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Publisher: Springer Science and Business Media LLC

Date: 23-07-2018

DOI: 10.1038/S41588-018-0147-3

Detection of mutations in theCOL4A5gene by SSCP in X-linked Alport syndrome

Publisher: Hindawi Limited

Date: 08-2001

DOI: 10.1002/HUMU.1163

Abstract: Alport syndrome is a progressive renal disease leading to chronic renal failure, which often is accompanied by sensorineural deafness and ophthalmological signs in the form of anterior lenticonus. The X-linked form of the disease is caused by mutations in the COL4A5 gene encoding the alpha5-chain of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X-linked inheritance, and 15 isolated cases. We found a mutation detection rate of 52% (42/81) (58% in males and 21% in females), and 69% (20/29) in families who clearly demonstrated X-linked inheritance. Thirty-six different mutations were found in 42 patients comprising 16 missense mutations, seven frameshifts, three in-frame deletions, four nonsense mutations, and six splice site mutations. Twenty-two of the mutations have not previously been reported. Furthermore, we found one non-pathogenic amino acid substitution, one rare variant in a non-coding region, and one polymorphism with a heterozygosity of 28%. Three de novo mutations were found, two of which were paternal and one of maternal origin.

P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation

Publisher: Springer Science and Business Media LLC

Date: 27-05-2011

DOI: 10.1186/1471-2407-11-203

Abstract: Metastatic melanoma represents a major clinical problem. Its incidence continues to rise in western countries and there are currently no curative treatments. While mutation of the P53 tumour suppressor gene is a common feature of many types of cancer, mutational inactivation of P53 in melanoma is uncommon however, its function often appears abnormal. In this study whole genome bead arrays were used to examine the transcript expression of P53 target genes in extracts from 82 melanoma metastases and 6 melanoma cell lines, to provide a global assessment of aberrant P53 function. The expression of these genes was also examined in extracts derived from diploid human melanocytes and fibroblasts. The results indicated that P53 target transcripts involved in apoptosis were under-expressed in melanoma metastases and melanoma cell lines, while those involved in the cell cycle were over-expressed in melanoma cell lines. There was little difference in the transcript expression of P53 target genes between cell lines with null/mutant P53 compared to those with wild-type P53 , suggesting that altered expression in melanoma was not related to P53 status. Similarly, down-regulation of P53 by short-hairpin RNA (shRNA) had limited effect on P53 target gene expression in melanoma cells, whereas there were a large number of P53 target genes whose mRNA expression was significantly altered by P53 inhibition in melanocytes. Analysis of whole genome gene expression profiles indicated that the ability of P53 to regulate genes involved in the cell cycle was significantly reduced in melanoma cells. Moreover, inhibition of P53 in melanocytes induced changes in gene expression profiles that were characteristic of melanoma cells and resulted in increased proliferation. Conversely, knockdown of P53 in melanoma cells resulted in decreased proliferation. These results indicate that P53 target genes involved in apoptosis and cell cycle regulation are aberrantly expressed in melanoma and that this aberrant functional activity of P53 may contribute to the proliferation of melanoma.

Detection of germline mutations in the BRCA1 gene by RNA-based sequencing

Publisher: Hindawi Limited

Date: 13-07-2001

DOI: 10.1002/HUMU.1164

Abstract: BRCA1 mutation detection is expensive and has sensitivity limitations, which might at least partially be overcome by RNA-based sequencing. There are claims that RNA tests are unreliable due to differential splicing, exon skipping, or nonsense-mediated mRNA decay that results in either the absence or low expression of mRNA harboring mutations. The major aim of this study was to determine if the application of specific high temperature annealing primers can assure high sensitivity of detection of BRCA1 sequence alterations by cDNA sequencing. The study group comprised 21 Polish cancer families with aggregations of breast and/or ovarian cancer. We detected mutations in 10 out of 21 unrelated patients. These were: nucleotide substitutions (c.309T>C c.300T>G) nucleotide insertions (c.5382insC) three cases nucleotide deletions (c.4154delA) one case, (c. 185delAG) one case, (c.3819delGTAAA) two cases and the deletion of the entire sequence of exon 22, one case. In addition, we identified three transcript variants resulting from alternative splice sites affecting the last six nucleotides of exon 1a (GTAAAG), and the first three nucleotides (CAG) of exon 8 and exon 14. In all cases these were cDNA heterozygous changes. Two of these splice site changes have not been previously described. Sequencing of genomic DNA "exon by exon" did not result in the detection of any additional abnormalities. The sensitivity of our analyses was sufficient to reliably detect mutations without the necessity of tissue culturing to obtain enough template cDNA for analysis.

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk

Publisher: Wiley

Date: 16-07-2019

DOI: 10.1002/IJC.32542

Abstract: A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Publisher: Springer Science and Business Media LLC

Date: 11-2019

DOI: 10.1038/S41523-019-0127-5

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.

Clinical and epidemiological features of familial laryngeal cancer in Poland

Publisher: Elsevier BV

Date: 2007

DOI: 10.1016/J.CDP.2006.06.007

Abstract: Laryngeal cancer has one of the worst recurrence rates for any malignancy, is known to be influenced by several environmental factors, and it is significantly more common in males than females. Familial clusterings of laryngeal cancer have been reported but no systematic evaluation of the clinical feature of the disease or an in-depth analysis of familial forms of the disease has been made. In this study we wished to determine if there are any clinical features of the disease that may be useful for the identification of genetic susceptibility loci associated with the disorder. Seven hundred and fifty-three unselected consecutive laryngeal cancer patients were analyzed depending on sex, age, smoking behavior, and clinical features (localization, tumor size, lymph node metastases, grading, and staging) and the presence of cancer among first-degree relatives. The presence of at least a second relative affected by laryngeal cancer was considered to be a Familial Larynx Cancer (FLC) case (44 patients). Women in the FLC group had larger tumors, higher proportion of lymph node metastases, higher grading, staging, and a tendency towards supraglottic localization than the sporadic larynx cancer cases. The aggressive pattern characterized by presence of metastases, tumor size >2, and grading=3 revealed to be significantly associated with FLC (OR=10.02, p=0.0003). The study revealed a distinct clinical pattern of disease in familial cases of laryngeal cancer, which may provide a valuable basis for the identification of genetic determinants of this malignancy.

MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood

Publisher: Public Library of Science (PLoS)

Date: 11-08-2010

DOI: 10.1371/JOURNAL.PONE.0012132

Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis

Publisher: SAGE Publications

Date: 03-08-2012

DOI: 10.1177/1352458511415562

Abstract: Background: The environmental influence of sun exposure and vitamin D in particular and its implication with multiple sclerosis (MS) has recently received considerable attention. Current evidence based on genetic and epidemiological studies indicate that vitamin D is implicated in the aetiology of this disease. Methods: We examined two common variants in the vitamin D receptor ( VDR) gene in 1153 trio families and 726 cases and 604 controls. We also examined epistatic interactions between the VDR SNPs rs731236 and rs2228570 with the tagging single nucleotide polymorphism (SNP) rs3135388 for the HLA-DRB*1501 locus containing a highly conserved vitamin D responsive element within its promoter region. Results: We found weak evidence for an association between the rs731236C allele and MS, while there was no direct association with rs2228570. When examining the interaction between the VDR gene variations and the DRB1*1501 tagging SNP a more complex relationship was observed. Although the interaction was not statistically significant, there appeared to be a trend of increasing risk of MS in participants who were homozygous for the HLA-DRB1*1501 allele in association with the more active form of the VDR (Fok1). Conclusion: We have identified weak evidence of an association between a common variation within the VDR gene and MS, in the largest study reported to date of this candidate gene. There appears to be a relationship between polymorphisms in the VDR and the risk of MS, which is potentially modified by HLA-DRB1*1501.

Capturing SNP Association across the NK Receptor and HLA Gene Regions in Multiple Sclerosis by Targeted Penalised Regression Models

Publisher: MDPI AG

Date: 29-12-2021

DOI: 10.3390/GENES13010087

Abstract: Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing s le sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subs ling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For ex le, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p 5 × 10−8) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.

Methylation of the Corticotropin Releasing Hormone Gene Promoter in BeWo Cells: Relationship to Gene Activity

Publisher: Hindawi Limited

Date: 2015

DOI: 10.1155/2015/861302

Abstract: Corticotropin releasing hormone (CRH) production by the human placenta increases exponentially as pregnancy advances, and the rate of increase predicts gestational length. CRH gene expression is regulated by cAMP in trophoblasts through a cyclic AMP-response element (CRE), which changes its transcription factor binding properties upon methylation. Here we determined whether methylation of the CRH proximal promoter controls basal and cAMP-stimulated CRH expression in BeWo cells, a well-characterized trophoblastic cell line. We treated the cells with 8-Br-cAMP and the DNA methyltransferase inhibitor 5-aza-2′ deoxycytidine (5-AZA-dC) and determined the effects on CRH mRNA level and promoter methylation. Clonal bisulfite sequencing showed partial and allele independent methylation of CpGs in the CRH promoter. CRH mRNA expression and the methylation of a subset of CpGs (including CpG2 in the CRE) increased spontaneously during culture. 8-Br-cAMP stimulated CRH expression without affecting the increase in methylation. 5-AZA-dC decreased methylation and augmented 8-Br-cAMP-stimulated CRH expression, but it blocked the spontaneous increase of CRH mRNA level. We conclude that the CRH promoter is a dynamically and intermediately methylated genomic region in BeWo cells. Promoter methylation did not inhibit CRH gene expression under the conditions employed rather it determined the contribution of alternative cAMP-independent pathways and cAMP-independent mechanisms to CRH expression control.

IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer

Publisher: Wiley

Date: 11-07-2008

DOI: 10.1002/IJC.23668

Abstract: Patients diagnosed with HNPCC harbouring a confirmed germline mutation in DNA mismatch repair (MMR) genes have an 80% lifetime risk of developing an epithelial malignancy. There is, however, considerable variation in the age of disease onset in these patients. Insulin-like growth factor-I (IGFI) has been implicated in colorectal cancer (CRC), and elevated plasma IGFI levels are associated with both sporadic and hereditary CRC risk. In this study, we further investigate the cytosine-adenine (CA) dinucleotide repeat polymorphism located near the promoter region of IGF1 and its relation to early onset CRC risk in 443 Australian and Polish MMR gene mutation carriers using DNA sequencing, Kaplan-Meier survival curves and Cox proportional hazard regression analysis. A significantly smaller number of IGF1 CA repeats was observed in the Polish patient population, which was associated with an earlier age of disease onset compared to the Australian patients. The threshold for the observed modifying effect was again shown to be in patients with 17 or less CA repeats compared to those with 18 or more. Furthermore, when MMR mutation group (i.e., MLH1 or MSH2), gender and family clustering were included in the final Cox model we observed a more robust trend for the role of the IGF1 CA repeat in predicting age of disease onset in HNPCC patients. In addition, this effect was shown to be equal in both MLH1 and MSH2 mutation carrier groups and not restricted to a particular MMR subgroup (p = 0.001). We conclude that the IGF1 CA repeat is an important modifier of disease onset in HNPCC and the first polymorphism to yield consistent results across different populations.

The prevalence of unique SNPs in the renin-angiotensin system highlights the need for pharmacogenetics in Indigenous Australians

Publisher: Wiley

Date: 28-01-2016

DOI: 10.1111/1440-1681.12525

Abstract: Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049) AGT G+174A (rs4762) Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186) angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292) renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous in iduals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.

Interleukin-10 and sudden infant death syndrome

Publisher: Oxford University Press (OUP)

Date: 09-2004

DOI: 10.1016/J.FEMSIM.2004.06.020

Immune responses of airway neutrophils are impaired in asthma

Publisher: Informa UK Limited

Date: 2009

DOI: 10.1080/01902140902777490

Abstract: Neutrophilic inflammation is a key effector arm of the innate immune response. Neutrophils may contribute significantly to airway inflammation in certain asthma subtypes. The objective of this study is to investigate the innate immune responses of isolated airway and circulating neutrophils in asthma. Participants with asthma (n = 17) and healthy volunteers (n = 11) underwent induced sputum and blood collection. Neutrophils were isolated from dispersed selected sputum and blood granulocytes using magnetic cell separation. Neutrophils were cultured with or without lipopolysaccharide (100 ng/mL) for 24 hours. Innate immune mediators were measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Airway neutrophils from participants with asthma spontaneously released lower levels of interleukin (IL)-8, IL-1beta and tumor necrosis factor-alpha proteins, and had lower levels of cytokine gene expression compared to healthy controls. Toll-like receptor 4 (TLR4) gene expression was significantly decreased in airway neutrophils from participants with asthma compared to healthy volunteers. Resting and lipopolysaccharide (LPS)-stimulated circulating neutrophils had lower levels of TLR2 and IL-1beta gene expression in asthma, but were otherwise similar to healthy controls. No differences were seen for matrix metalloproteinase (MMP)-9 release in asthma. Innate immune responses of airway neutrophil cells are impaired in asthmatic subjects on prophylactic therapy and may impact on susceptibility to, and severity of, airway infections.

MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients

Publisher: Wiley

Date: 09-11-2007

DOI: 10.1002/IJC.22339

Abstract: Disease expression in hereditary nonpolyposis colorectal cancer (HNPCC) cannot be readily explained by mutation site in the respective DNA mismatch repair genes associated with this disorder. One explanation is the role of modifying genes that can either promote or prevent disease development on a background of increased risk. Two single nucleotide polymorphisms in MDM2 and TP53 have been shown to be associated with younger ages of disease onset in HNPCC (TP53) and Li-Fraumeni syndrome (MDM2). In this study 220 HNPCC patients were examined, from Australia and Poland, all characterized at the molecular level to determine the frequency of the MDM2 SNP309 T>G and to assess its influence on disease expression. The results were then pooled with the results of a previous study to assess the combined influence of the MDM2 SNP309 T>G and TP53 SNP R72P. A significant difference was observed between CRC patients and unaffected MMR gene mutation carriers over the age of 45 years (p = 0.01). The unaffected MMR gene mutation carriers over the age of 45 years who carry the G allele have a reduced risk of developing CRC. The results indicate that the MDM2 SNP309, alone or in combination with TP53 R72P, does not influence age of diagnosis of CRC in in iduals with HNPCC. In conclusion, the data indicates the G allele of MDM2 SNP309 might have a protective effect on disease development in HNPCC patients and that age of diagnosis of CRC is not associated with MDM2 SNP309 or TP53 R72P either as single SNPs or combined.

Erratum: COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 2010

DOI: 10.1038/SJ.BJC.6605518

Concentrations of plasma-borne extracellular particles differ between multiple sclerosis disease courses and compared to healthy controls

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.MSARD.2020.102446

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Publisher: Springer Science and Business Media LLC

Date: 16-06-2020

DOI: 10.1038/S41598-020-65665-Y

Abstract: In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non- BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859–1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482–1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

Genome-wide association meta-analysis identifies new endometriosis risk loci

Publisher: Springer Science and Business Media LLC

Date: 28-10-2012

DOI: 10.1038/NG.2445

Genome-wide DNA methylation profiling of CD8+ T cells shows a distinct epigenetic signature to CD4+ T cells in multiple sclerosis patients

Publisher: Springer Science and Business Media LLC

Date: 05-11-2015

DOI: 10.1186/S13148-015-0152-7

Molecular patterns of cancer colonisation in lymph nodes of breast cancer patients

Publisher: Springer Science and Business Media LLC

Date: 20-11-2018

DOI: 10.1186/S13058-018-1070-3

Erratum: Germline 657del5 mutation in the NBSI gene in breast cancer patients (International Journal Cancer (2003) 106 (379-381))

Publisher: Wiley

Date: 06-08-2003

DOI: 10.1002/IJC.11439

A polymorphic repeat in the IGF1 promoter influences the risk of endometrial cancer

Publisher: Bioscientifica

Date: 05-2016

DOI: 10.1530/EC-16-0003

Abstract: Due to the lack of high-throughput genetic assays for tandem repeats, there is a paucity of knowledge about the role they may play in disease. A polymorphic CA repeat in the promoter region of the insulin-like growth factor 1 gene ( IGF1 has been studied extensively over the past 10 years for association with the risk of developing breast cancer, among other cancers, with variable results. The aim of this study was to determine if this CA repeat is associated with the risk of developing breast cancer and endometrial cancer. Using a case–control design, we analysed the length of this CA repeat in a series of breast cancer and endometrial cancer cases and compared this with a control population. Our results showed an association when both alleles were considered in breast and endometrial cancers ( P =0.029 and 0.011, respectively), but this did not pass our corrected threshold for significance due to multiple testing. When the allele lengths were analysed categorically against the most common allele length of 19 CA repeats, an association was observed with the risk of endometrial cancer due to a reduction in the number of long alleles ( P =0.013). This was confirmed in an analysis of the long alleles separately for endometrial cancer risk ( P =0.0012). Our study found no association between the length of this polymorphic CA repeat and breast cancer risk. The significant association observed between the CA repeat length and the risk of developing endometrial cancer has not been previously reported.

Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Publisher: Wiley

Date: 23-02-2019

DOI: 10.1002/AJMG.B.32716

Vitamin D receptor variants and breast cancer risk in the Polish population

Publisher: Springer Science and Business Media LLC

Date: 29-06-2009

DOI: 10.1007/S10549-008-0107-1

Abstract: The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the in idual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33-2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71-3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.

Maternal use of folic acid and other supplements and risk of childhood brain tumors

Publisher: American Association for Cancer Research (AACR)

Date: 11-2012

DOI: 10.1158/1055-9965.EPI-12-0803

Abstract: Background: Interest in a possible protective effect of maternal vitamin use before or during pregnancy against childhood brain tumors (CBT) and other childhood cancers has grown over the past decade. Our Australian study of CBTs, conducted between 2005 and 2011, investigated whether maternal use folic acid and other supplements was protective. Methods: Case children were identified through the 10 Australian pediatric oncology centers and controls were recruited by national random digit dialing. Mothers of 327 cases and 867 control children provided information on supplement use before and during the index pregnancy, including brand name, dose, and timing. Data were analyzed using multivariable unconditional logistic regression. Results: The OR for any maternal use of folic acid, use of folic acid without iron or vitamins B6, B12, C, or A, and any vitamin use before pregnancy, were: 0.68 [95% confidence interval (CI), 0.46–1.00 0.55 (95% CI, 0.32–0.93) and 0.68 (95% CI, 0.46–1.01), respectively. The ORs for use of these supplements during pregnancy were also below unity, but generally closer to the null than those for the prepregnancy period. There was some evidence of an inverse dose–response during each time period. Conclusions: These results suggest that folic acid supplements before and possibly during pregnancy may protect against CBT. Such associations are biologically plausible through established mechanisms. Impact: This study provides evidence of a specific protective effect of prenatal folic acid supplementation against the risk of CBT that is not attributable to the actions of the other micronutrients investigated. Cancer Epidemiol Biomarkers Prev 21(11) 1933–41. ©2012 AACR.

Enrichment of atypical hyperdiploidy and IKZF1 deletions detected by SNP-microarray in high-risk Australian AIEOP-BFM B-cell acute lymphoblastic leukaemia cohort

Publisher: Elsevier BV

Date: 04-2020

DOI: 10.1016/J.CANCERGEN.2020.01.051

Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia

Publisher: Public Library of Science (PLoS)

Date: 27-04-2012

DOI: 10.1371/JOURNAL.PONE.0036351

Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility

Publisher: Public Library of Science (PLoS)

Date: 08-02-2011

DOI: 10.1371/JOURNAL.PONE.0016964

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Publisher: Springer Science and Business Media LLC

Date: 02-2015

DOI: 10.1038/MP.2014.188

Abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts ( N =53 949) in which the participants had undertaken multiple, erse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P =3.93 × 10 −9 , MIR2113 rs17522122, P =2.55 × 10 −8 , AKAP6 rs10119, P =5.67 × 10 −9 , APOE/TOMM40 ). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 ( P =1 × 10 −6 ). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study ( N =6617) and the Health and Retirement Study ( N =5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort ( N =5487 P =1.5 × 10 −17 ). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40 , APOE , ABCG1 and MEF2C .

Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes.

Publisher: BMJ

Date: 05-1995

DOI: 10.1136/GUT.36.5.731

Abstract: The APC gene is mutated in the germline of people from families where there is a predisposition to develop polyposis coli. Many mutations have been described but the relation between their site and the phenotypic expression of the disease remains unclear. The most commonly seen mutation occurs at codon 1309. Many other mutations have been described towards the 5' end of exon 15 of the APC gene but comparatively few have been seen towards the 3' end. Recent reports have indicated the possibility of a functional boundary with respect to severity and age of onset of disease, which lies towards the 5' end of the gene. This report describes a large family whose affected members present with a very variable phenotype ranging from an early onset and severe form to a comparatively mild later onset one. The mutation that predisposes to disease in this family is at a previously undescribed site that lies towards the 3' end of exon 15 of the APC gene, which results in a stop codon. Interestingly, the stop codon is 63 codons downstream of the mutation and therefore may affect the expression of the disease. The addition of this mutation to the growing list of mutations described in the APC gene may provide some insight into the genotype henotype relation of the disease thus contributing to the understanding and significance of mutations at specific sites in the APC gene.

Extracellular matrix (ECM) activates β-catenin signaling in uterine fibroids.

Publisher: Bioscientifica

Date: 07-2017

DOI: 10.1530/REP-17-0339

Abstract: κΩΨ¥–€™±≈‰ greater than less than Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/β-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a comprehensive analysis of the WNT pathway in MED12-mutated and MED12-wild type fibroids has not been performed. The objective of this study was to determine the status of the WNT pathway in human fibroids. We performed Sanger sequencing to define the MED12 mutational status of fibroids and normal myometrium s les. qPCR arrays were carried out to determine the status of the WNT signaling pathway in MED12-mutated and MED12-wild type fibroids. Liquid chromatography-mass spectrometry (LC-MS), western blotting, and immunohistochemistry were used to monitor the expression of β-catenin. We showed that β-catenin expression was increased in fibroids compared to the adjacent myometrium s les. However, β-catenin expression showed no correlation with MED12 mutation status. Of all the WNT signaling components, WNT inhibitors showed the greatest differences in expression between fibroids and controls. WIF1, a WNT inhibitor, was identified as the most significantly upregulated gene in fibroids. We cultured primary fibroid cells on hydrogels of known stiffness to decipher the influence of biomechanical cues on β-catenin expression and revealed increased levels of β-catenin when cells were cultured on a stiffer surface. In conclusion, our data showed tha t β-catenin expression in fibroids occurs independently of MED12 mutations. Biomechanical changes upregulate β-catenin expression in fibroids, pro viding an attractive avenue for developing new treatments for this disease.

Phenotype-genotype correlations in a series of Wolfram syndrome families

Publisher: American Diabetes Association

Date: 08-2004

DOI: 10.2337/DIACARE.27.8.2003

Abstract: OBJECTIVE—Wolfram syndrome is an extremely rare autosomal-recessive disorder that predisposes the development of type 1 diabetes in association with progressive optic atrophy. The genetic basis of this disease has been shown to be due to mutations in the WFS1 gene. The WFS1 gene encodes a novel transmembrane protein called wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. Genotype-phenotype correlations in this syndrome are becoming apparent and may help in explaining some of the variable characteristics observed in this disease. RESEARCH DESIGN AND METHODS—In this report, we have studied 13 patients with Wolfram syndrome from nine families to further define the relationship between mutation site and type with specific disease characteristics. RESULTS—A severe phenotype was seen in patients with mutations in exon 4 and with a large deletion encompassing most of exon 8. In total, nine novel mutations were identified as well as three new silent polymorphisms. CONCLUSIONS—Similar to all other mutation reports, most causative changes identified in the WFS1 gene occurred in exon 8, and only one was identified outside this region in exon 4.

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Publisher: Springer Science and Business Media LLC

Date: 30-01-2017

DOI: 10.1038/NG.3768

Colorectal cancer: lessons for genetic counselling and care for families

Publisher: Wiley

Date: 07-1994

DOI: 10.1111/J.1399-0004.1994.TB04212.X

Abstract: Cancers of the colon and the rectum are the second leading cause of malignancy in European countries with similar incidence rates for men and women and, therefore, one of the major health concerns. Emphasis is placed on the early detection of a developing neoplasm in order to improve the life expectancy of patients and their quality of life. Colorectal cancer (CRC) is an excellent model for studying the etiology and pathogenesis of a common malignancy and the complex multistage process of carcinogenesis. Abundant clinical and pathological evidence suggests that CRC arises from benign adenomas that proceed through a series of steps to metastatic carcinomas. Following the discovery of oncogenes and, more importantly tumor suppressor genes, Fearon & Vogelstein (1990) proposed a scheme of genetic events which are associated with colorectal tumorigenesis. Genetic linkage studies have recently identified another type of gene for colon cancer susceptibility that seems to act by destabilising the genome.

Identification of Genome-Wide SNP–SNP and SNP–Clinical Boolean Interactions in Age-Related Macular Degeneration

Publisher: Springer New York

Date: 03-11-2014

DOI: 10.1007/978-1-4939-2155-3_12

Abstract: We propose here a methodology to uncover modularities in the network of SNP-SNP interactions most associated with disease. We start by computing all possible Boolean binary SNP interactions across the whole genome. By constructing a weighted graph of the most relevant interactions and via a combinatorial optimization approach, we find the most highly interconnected SNPs. We show that the method can be easily extended to find SNP/environment interactions. Using a modestly sized GWAS dataset of age-related macular degeneration (AMD), we identify a group of only 19 SNPs, which include those in previously reported regions associated to AMD. We also uncover a larger set of loci pointing to a matrix of key processes and functions that are affected. The proposed integrative methodology extends and overlaps traditional statistical analysis in a natural way. Combinatorial optimization techniques allow us to find the kernel of the most central interactions, complementing current methods of GWAS analysis and also enhancing the search for gene-environment interaction.

Familial and genetic aspects of colorectal carcinogenesis

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/0959-8049(93)90056-L

Abstract: There is abundant clinical and pathological evidence which suggests that colorectal cancer arises in a sequential manner through a series of events that can be followed during the progression of the disease from early adenoma through to metastatic disease. The molecular events that are associated with the initiation and progression of the disease are gradually being unravelled. As the molecular characterisation of colorectal cancer continues, new mechanisms by which the disease progresses are becoming evident. In this short review, a brief description of current knowledge of colorectal cancer development is presented.

Comparison of cytokine gene polymorphisms among Greek patients with invasive meningococcal disease or viral meningitis

Publisher: Microbiology Society

Date: 05-2013

DOI: 10.1099/JMM.0.058073-0

Abstract: High levels of pro-inflammatory cytokines are implicated in the severity of invasive meningococcal disease (IMD) and viral meningitis (VM). This study compared single-nucleotide polymorphisms (SNPs) in pro- and anti-inflammatory cytokine genes among patients with VM or IMD. Patient DNA s les were prepared by the National Meningitis Reference Laboratory in Athens: n = 98 for IMD and n = 53 for VM. The results for both patient groups were compared with data published for healthy Greek control data. Real-time PCR was used to assess the interleukin (IL) gene SNPs IL6 G−174C, IL1B C−511T, IL1RN T+2018C, IL10 G−1082A and IL8 A−251T and the tumour necrosis factor α (TNF-α) SNP TNFA G−308A. Differences were compared by Fisher’s exact test. The genotype for high IL-6 responses was predominant among IMD (51 %, P = 0.0008) and VM (74.5 %, P .0001) patients compared with the controls (31 %). The genotype associated with high TNF-α responses was 5 % among controls and lower for IMD (1.1 %, P = 0.0014) and VM (0 %, P = 0.052). There was no difference for IL-8 SNPs between controls and IMD ( P = 0.162), but the difference was significant for VM ( P = 0.0025). IL-6 ( P = 0.024) and IL-8 ( P = 0.00004) SNPs differed between IMD and VM. Reports on associations between IL-8 SNPs and cytokine responses differ. Because of its role in neutrophil attraction, differences in frequencies of the IL-8 SNP for IMD and VM require further investigation.

RAD51B in Familial Breast Cancer

Publisher: Public Library of Science (PLoS)

Date: 05-05-2016

DOI: 10.1371/JOURNAL.PONE.0153788

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium

Publisher: Elsevier BV

Date: 11-2018

DOI: 10.1016/J.BIOPSYCH.2018.04.023

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Publisher: Elsevier BV

Date: 06-2018

DOI: 10.1016/J.AJHG.2018.11.002

The male excess in sudden infant deaths

Publisher: SAGE Publications

Date: 22-04-2013

DOI: 10.1177/1753425913481071

Abstract: The peak age at which sudden infant death syndrome (SIDS) occurs corresponds to the developmental period in which infants are dependent on their innate responses to infection. There is a growing body of evidence indicating that dysregulation of inflammatory responses might contribute to the physiological changes leading to these sudden deaths. This study examined the effects of three important risk factors for SIDS on inflammatory responses: cigarette smoke, virus infection and male sex. Cytokine responses of peripheral monocytic blood cells of healthy, non-smoking males and females to endotoxin were measured. Surrogates for virus infection or cigarette smoke were assessed using IFN-γ or water-soluble cigarette smoke extract (CSE). For most conditions, cells from males had lower pro-inflammatory cytokine responses than those of females. An opposite trend was observed for IL-10. Significantly lower levels of some cytokines were noted for cells from male donors exposed to CSE. In females, there were significant correlations between testosterone levels and levels of pro-inflammatory cytokines, but none for males. Testosterone levels in females correspond to those among male infants in the age range at greatest risk of SIDS. The effects of the testosterone surge in male infants need to be examined in relation to changes in cortisol levels that occur during the same period of infant development.

BRCA2 mutations in a population-based series of patients with ocular melanoma

Publisher: Wiley

Date: 13-09-2002

DOI: 10.1002/IJC.10693

Abstract: We studied the BRCA2 gene for germline mutations in 71 of 99 patients (72%) with ocular melanoma who were diagnosed consecutively in Australia in 1997 and 1998. Patients considered for our study fulfilled one of the following critiera: (i) were 50 years of age or less at diagnosis (ii) had bilateral disease (2 patients) (iii) reported a family history of ocular melanoma (4 patients). Mutation detection was performed using the protein truncation test and denaturing high-performance liquid chromatography with primers designed to include intron-exon boundaries. Six DNA changes were found of which 2 were exonic, in exons 14 (A>C in nucleotide 7244 leading to His>Arg) and 27 (base pair substitution in nucleotide 9976 leading to a stop codon). One exonic change has been reported previously. None of the intronic mutations were deemed to affect splicing efficiency. Neither exonic mutation was in a person with bilateral ocular melanoma or a family history of cutaneous melanoma. We estimated the prevalence of possible loss of function changes in BRCA2 in patients with ocular melanoma at 3% (95% CI 0-10%). This figure was similar to previous estimates of 2.8% and 2% in nonrepresentative s les of patients with ocular melanoma and 2.1% in a representative s le of young women with breast cancer.

Low-level parental mosaicism in an apparent de novo case of Peutz–Jeghers syndrome

Publisher: Springer Science and Business Media LLC

Date: 14-06-2019

DOI: 10.1007/S10689-018-0093-3

Abstract: We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz-Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Publisher: Oxford University Press (OUP)

Date: 13-06-2014

DOI: 10.1093/HMG/DDU300

Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

Publisher: Springer Science and Business Media LLC

Date: 11-08-2010

DOI: 10.1186/1471-2407-10-420

Abstract: CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Publisher: Springer Science and Business Media LLC

Date: 29-05-2018

DOI: 10.1038/S41467-018-04362-X

Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486 age 16–102) and find 148 genome-wide significant independent loci ( P 5 × 10 −8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent s les. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Survival of Patients with Turcot's Syndrome and Glioblastoma

Publisher: Massachusetts Medical Society

Date: 14-03-1996

DOI: 10.1056/NEJM199603143341118

Abstract: Zymomonas mobilis is an ethanologenic bacterium currently being developed for production of advanced biofuels. Recent studies have shown that Z. mobilis can fix dinitrogen gas (N

Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis

Publisher: Elsevier BV

Date: 03-2016

DOI: 10.1016/J.BBI.2015.12.010

Abstract: Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia (SZ n=47) cases representing both 'cognitive deficit' (CD n=22) and 'cognitively spared' (CS n=25) subtypes of schizophrenia (based on latent class analysis of 9 cognitive performance indicators), compared with 49 healthy controls displaying 'normal' cognition. This was accomplished using gene-set analysis of transcriptome data derived from peripheral blood mononuclear cells (PBMCs). We detected 27 significantly altered pathways (19 pathways up-regulated and 8 down-regulated) in the combined SZ group and a further 6 pathways up-regulated in the CS group and 5 altered pathways (4 down-regulated and 1 up-regulated) in the CD group. The transcriptome profiling in SZ and cognitive subtypes were characterized by the up-regulated pathways involved in immune dysfunction (e.g., antigen presentation in SZ), energy metabolism (e.g., oxidative phosphorylation), and down-regulation of the pathways involved in neuronal signaling (e.g., WNT in SZ/CD and ERBB in SZ). When we looked for pathways that differentiated the two cognitive subtypes we found that the WNT signaling was significantly down-regulated (FDR<0.05) in the CD group in accordance with the combined SZ cohort, whereas it was unaffected in the CS group. This suggested suppression of WNT signaling was a defining feature of cognitive decline in schizophrenia. The WNT pathway plays a role in both the development/function of the central nervous system and peripheral tissues, therefore its alteration in PBMCs may be indicative of an important genomic axis relevant to cognition in the neuropathology of schizophrenia.

Buccal DNA Collection : Comparison of Buccal Swabs with FTA Cards

Publisher: American Association for Cancer Research (AACR)

Date: 04-2006

DOI: 10.1158/1055-9965.EPI-05-0753

Abstract: Collection and analysis of DNA, most commonly from blood or buccal cells, is becoming more common in epidemiologic studies. Buccal s les, which are painless to take and relatively easily collected, are often the preferred source. There are several buccal cell collection methods: swabs, brushes, mouthwash, and treated cards, such as FTA or IsoCode cards. Few studies have systematically compared methods of buccal cell collection with respect to DNA yield and lification success under similar conditions. We compared buccal DNA collection and lification using buccal swabs and FTA cards in 122 control subjects from our Australian case-control study of childhood acute lymphoblastic leukaemia. Buccal DNA was quantified using a real-time PCR for β-actin and genotyped at the loci of three polymorphisms (MTHFR 677C& T, ACE I/D, and XPD 1012G& A). PCR was successful with DNA from buccal swabs for 62% to 89% of subjects and from FTA cards for 83% to 100% of subjects, depending on the locus. The matched pair odds ratios (95% confidence interval) comparing success of FTA cards with buccal swabs are as follows: MTHFR 677C& T using PCR-RFLP, 12.5 (11.6-13.5) and using real-time PCR, 130.0 (113.1-152.8) ACE I/D using PCR- lified fragment length polymorphism, 3.36 (3.2-3.5) XPD 1012G& A using real-time PCR, 150.0 (132.7-172.3). FTA cards are a robust DNA collection method and generally produce DNA suitable for PCR more reliably than buccal swabs. There are, however, technical challenges in handling discs punched from FTA cards that intending users should be aware of. (Cancer Epidemiol Biomarkers Prev 2006 (4):816–9)

Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer

Publisher: Springer Science and Business Media LLC

Date: 02-2015

DOI: 10.1007/S10549-015-3293-7

Abstract: Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours in women with BRCA1 mutations. Reports to date indicate that up to 20 % of TNBC patients harbour germline BRCA mutations however, the prevalence of BRCA mutations in TNBC patients varies widely between countries and from study to study. We studied 774 women with triple-negative breast cancer, diagnosed on average at age 58.0 years. S les of genomic DNA were provided by the Australian Breast Cancer Tissue Bank (ABCTB) (439 patients) and by the Department of Genetics and Pathology of the Pomeranian Medical University (335 patients). The entire coding regions and the exon-intron boundaries of BRCA1 and BRCA2 were lified and sequenced by next-generation sequencing. We identified a BRCA1 or BRCA2 mutation in 74 of 774 (9.6 %) triple-negative patients. The mutation prevalence was 9.3 % in Australia and was 9.9 % in Poland. In both countries, the mean age of diagnoses of BRCA1 mutation carriers was significantly lower than that of non-carriers, while the age of onset of BRCA2 mutation carriers was similar to that of non-carriers. In the Australian cohort, 59 % of the mutation-positive patients did not have a family history of breast or ovarian cancer, and would not have qualified for genetic testing. The triple-negative phenotype should be added as a criterion to genetic screening guidelines.

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Publisher: Wiley

Date: 11-01-2016

DOI: 10.1002/MGG3.198

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Publisher: Elsevier BV

Date: 12-2012

DOI: 10.1016/S1470-2045(12)70475-8

Genetic burden associated with varying degrees of disease severity in endometriosis

Publisher: Oxford University Press (OUP)

Date: 16-04-2015

DOI: 10.1093/MOLEHR/GAV021

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Publisher: Cold Spring Harbor Laboratory

Date: 25-05-2018

DOI: 10.1101/329052

Abstract: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Published and in idual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Fourteen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95%CI 0.42 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95%CI 0.86 0.93). For ischemic stroke ORs were 0.84 (95%CI 0.57 1.22) for the GS, compared to 0.85 (95%CI 0.78 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11 1.50) for the GS, as compared to 1.00 (95%CI 0.96 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. Apparent discordance between genetic associations and trial outcome for T2DM might be explained lack by a of statistical precision, or differences in the nature and duration of genetic versus pharmacological perturbation of PCSK9. This research was funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456, FS/18/23/33512), UCL Hospitals NIHR Biomedical Research Centre, by the Rosetrees and Stoneygate Trusts. Evidence on the long-term efficacy and safety of therapeutic inhibition of PCSK9 is lacking. To explore potential long-term effects of PCSK9 inhibition, we characterised the phenotypic consequence of LDL-cholesterol lowering variants at the PCSK9 locus. A PCSK9 gene score comprising 4 SNPs recapitulated the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and risk of myocardial infarction, and was associated with an increased risk of type 2 diabetes. No associations with safety outcomes such as cancer, COPD, Alzheimer’s disease or atrial fibrillation were identified. Our findings suggest PCSK9 inhibition may be safe and effective during prolonged use.

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

Publisher: Elsevier BV

Date: 04-2019

DOI: 10.1016/J.BIOPSYCH.2018.10.003

The effect of a muscarinic receptor 1 gene variant on grey matter volume in schizophrenia

Publisher: Elsevier BV

Date: 11-2015

DOI: 10.1016/J.PSCYCHRESNS.2015.09.004

Abstract: Previous research has demonstrated that in iduals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test (WCST) than those who are heterozygous. This study sought to determine whether variation in the rs2067477 genotype was associated with differential changes in brain structure. Data from 227 patients with established schizophrenia or schizoaffective disorder were obtained from the Australian Schizophrenia Research Bank. Whole-brain voxel-based morphometry was performed to compare regional grey matter volume (GMV) between the 267C/C (N=191) and 267C/A (N=36) groups. Secondary analyses tested for an effect of genotype on cognition (the WCST was not available). In iduals who were homozygous (267C/C) demonstrated significantly reduced GMV in the right precentral gyrus compared to those who were heterozygous (267C/A). These preliminary results suggest that the rs2067477 genotype is associated with brain structure in the right precentral gyrus in in iduals with schizophrenia/schizoaffective disorder. Future studies are required to replicate these results and directly link the volumetric reductions with specific cognitive processes.

Association analysis identifies 65 new breast cancer risk loci.

Publisher: Springer Science and Business Media LLC

Date: 23-10-2017

DOI: 10.1038/NATURE24284

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

Publisher: Springer Science and Business Media LLC

Date: 02-02-2015

DOI: 10.1038/NCOMMS6899

Abstract: Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal s les. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

Altered expression of regulator of G-protein signalling 4 (RGS4) mRNA in the superior temporal gyrus in schizophrenia

Publisher: Elsevier BV

Date: 2007

DOI: 10.1016/J.SCHRES.2006.09.003

Abstract: To identify altered mRNA expression of regulator of G-protein signalling 4 (RGS4) in the superior temporal gyrus (STG) in schizophrenia mRNA expression of RGS4 was measured from post-mortem STG tissue from 13 in iduals with schizophrenia and 13 matched non-psychiatric controls using relative real-time PCR. Significantly decreased expression of RGS4 mRNA in the STG in schizophrenia was identified in 10 of the 13 matched pairs. Altered expression of RGS4 in cortical regions previously implicated in schizophrenia, such as the STG further supports the notion of RGS4 as a potential genetic and functional biological marker of schizophrenia.

Re: IGF-1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer [1]

Publisher: Oxford University Press (OUP)

Date: 15-11-2006

DOI: 10.1093/JNCI/DJJ452

Breastfeeding and nutrition to 2 years of age and risk of childhood acute lymphoblastic leukemia and brain tumors

Publisher: Informa UK Limited

Date: 03-02-2015

DOI: 10.1080/01635581.2015.998839

Abstract: Acute lymphoblastic leukemia (ALL) and childhood brain tumors (CBT) are 2 of the most common forms of childhood cancer, but little is known of their etiology. In 2 nationwide case-control studies we investigated whether breastfeeding, age of food introduction, or early diet are associated with the risk of these cancers. Cases aged 0-14 years were identified from Australian pediatric oncology units between 2003 and 2007 (ALL) and 2005 and 2010 (CBT) and population-based controls through nationwide random-digit dialing. Mothers completed questionnaires giving details of infant feeding up to the age of 2 yr. Data from 322 ALL cases, 679 ALL controls, 299 CBT cases, and 733 CBT controls were analysed using unconditional logistic regression. Breastfeeding was associated with a reduced risk of ALL [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.32, 0.84), regardless of duration. Introduction of artificial formula within 14 days of birth was positively associated with ALL (OR = 1.57, 95% CI: 1.03, 2.37), as was exclusive formula feeding to 6 mo (OR = 1.81, 95% CI: 1.07, 3.05). No associations were seen between breastfeeding or formula use and risk of CBT. Our results suggest that breastfeeding and delayed introduction of artificial formula may reduce the risk of ALL but not CBT.

Two truncating variants in FANCC and breast cancer risk

Publisher: Springer Science and Business Media LLC

Date: 29-08-2019

DOI: 10.1038/S41598-019-48804-Y

Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC , has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1 , BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring

Publisher: Wiley

Date: 23-03-2010

DOI: 10.1002/IJC.24969

Abstract: The Australian Study of Causes of Acute Lymphoblastic Leukemia in Children (Aus-ALL) was designed to test the hypothesis, raised by a previous Western Australian study, that maternal folic acid supplementation during pregnancy might reduce the risk of childhood acute lymphoblastic leukemia (ALL). Aus-ALL was a national, population-based, multicenter case-control study that prospectively recruited 416 cases and 1,361 controls between 2003 and 2007. Detailed information was collected about maternal use of folic acid and other vitamin supplements before and during the index pregnancy. Data were analyzed using logistic regression, adjusting for matching factors and potential confounders. A meta-analysis with the results of previous studies of folic acid supplementation was also conducted. We found weak evidence of a protective effect of maternal folate supplementation before pregnancy against risk of childhood ALL, but no evidence for a protective effect of its use during pregnancy. A meta-analysis including this and 2 other studies, but not the study that raised the hypothesis, also found little evidence that folate supplementation during pregnancy protects against ALL: the summary odds ratios (ORs) for folate supplementation were 1.06 [95% confidence interval (CI): 0.77-1.48] with reference to no folate supplementation and 1.02 (95% CI: 0.86-1.20) with reference to no vitamin supplementation. For vitamin supplementation in general, the summary OR from a meta-analysis of 5 studies-including Aus-ALL-was 0.83 (95% CI: 0.73-0.94). Vitamin supplementation in pregnancy may protect against childhood ALL, but this effect is unlikely to be large or, if real, specifically due to folate.

When is a mutation not a mutation: The case of the c.594-2A>C splice variant in a woman harbouring another BRCA1 mutation in trans

Publisher: Springer Science and Business Media LLC

Date: 16-02-2016

DOI: 10.1186/S13053-015-0045-Y

Abstract: Since the identification of BRCA1 there has only ever been described two bi-allelic mutation carriers, one of whom was subsequently shown to be a mono-allelic carrier. The second patient diagnosed with two BRCA1 mutations appears to be accurate but there remain some questions about the missense variant identified in that patient. In this report we have identified a woman who is a bi-allelic mutation carrier of BRCA1 and provide an explanation as to why this patient has a phenotype very similar to that of any mono-allelic mutation carrier. The splice variant identified in this patient appears to be associated with the up-regulation of a BRCA1 splice variant that rescues the lethality of being a double mutant. The consequences of the findings of this report may have implications for mutation interpretation and that could serve as a model for not only BRCA1 but also for other autosomal dominant disorders that are considered as being embryonically lethal.

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Publisher: Bioscientifica

Date: 16-11-2015

DOI: 10.1530/ERC-15-0386

Abstract: Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E 2 ) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P =4.8×10 −11 ). SNP rs727479 was also among those most strongly associated with circulating E 2 concentrations in 2767 post-menopausal controls ( P =7.4×10 −8 ). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E 2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E 2 . From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI ( P interaction =0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Proteomic Profiling of Human Uterine Fibroids Reveals Upregulation of the Extracellular Matrix Protein Periostin.

Publisher: The Endocrine Society

Date: 13-12-2018

DOI: 10.1210/EN.2017-03018

Abstract: The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, very little is known about patterns of ECM protein expression in fibroids and whether these are influenced by the most common genetic anomalies, which relate to MED12. We performed extensive genetic and proteomic analyses of clinically annotated fibroids and adjacent normal myometrium to identify the composition and expression patterns of ECM proteins in MED12 mutation–positive and mutation–negative uterine fibroids. Genetic sequencing of tissue s les revealed MED12 alterations in 39 of 65 fibroids (60%) from 14 patients. Using isobaric tagged–based quantitative mass spectrometry on three selected patients (n = 9 fibroids), we observed a common set of upregulated (& .5-fold) and downregulated (& .66-fold) proteins in small, medium, and large fibroid s les of annotated MED12 status. These two sets of upregulated and downregulated proteins were the same in all patients, regardless of variations in fibroid size and MED12 status. We then focused on one of the significant upregulated ECM proteins and confirmed the differential expression of periostin using western blotting and immunohistochemical analysis. Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status. This study sets the foundation for further investigations to analyze the mechanisms regulating ECM overexpression and the functional role of upregulated ECM proteins in leiomyogenesis.

Associations between methylenetetrahydrofolate reductase polymorphisms, serum homocysteine levels, and incident cortical cataract

Publisher: American Medical Association (AMA)

Date: 05-2016

DOI: 10.1001/JAMAOPHTHALMOL.2016.0167

Abstract: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels homocysteine has been implicated as a cataractogenic stressor. To investigate the associations of MTHFR polymorphisms and serum homocysteine levels with incident cortical cataract in an older population. From 1992 to 1994, a population-based cohort study, the Blue Mountains Eye Study, was conducted with 3654 residents (82.4% of eligible participants) of the Blue Mountains region aged 49 years and older. At the second (1997-1999, 5-year follow-up) and third (2002-2004, 10-year follow-up) surveys, 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were examined, respectively. For this report, the second survey serves as baseline when homocysteine levels were assessed, and 5-year incidence of cataract refers to incidence estimated from the second to the third survey. After excluding participants with no follow-up data or DNA or who had previous cortical cataract or cataract surgery, 757 participants were included in gene and environment analyses. This current project on associations with cataract was designed initially March 19, 2013, and completed April 14, 2014. Cataract was assessed using the Wisconsin Cataract Grading system. Two MTHFR polymorphisms, C677T (rs1801133) and A1298C (rs1801131), were included. Serum homocysteine levels were assessed following standard methods. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals for incident cortical cataract, after adjusting for age, sex, smoking status, hypertension, diabetes, education, and myopia. Path analysis was performed to explore a possible pathway of MTHFR polymorphisms via homocysteine levels to cortical cataract. The mean (SD) age of the 1726 participants in the Blue Mountains Eye Study 2 cohort with normal homocysteine levels was 68.3 (8.1) years and 73.2 (8.5) years for those with elevated homocysteine levels. Both the C677T polymorphism (CT/TT vs CC: OR = 1.50 95% CI = 1.01-2.23) and elevated homocysteine levels (>15 µmol/L: OR = 2.24 95% CI = 1.38-3.63) were independently associated with increased risk of cortical cataract. Path analysis showed that the genetic effect on cortical cataract was partially mediated via homocysteine levels. Combined CT/TT genotypes and elevated homocysteine levels were associated with a 3-fold risk of cortical cataract (OR = 3.74 95% CI = 1.79-7.80). The synergy index of both exposures was 1.34 (95% CI = 0.44-4.01). MTHFR polymorphism and elevated homocysteine levels contributed separately and jointly to increased risk of cortical cataract. If these findings are confirmed, homocysteine levels may be a therapeutic target to reduce risk of cortical cataract in persons carrying genetic risk.

A requirement for DNA synthesis in foetal hepatocyte differentiation: Effect of cytosine arabinoside on the appearance of the liver isoenzyme of pyruvate kinase

Publisher: Elsevier BV

Date: 11-1984

DOI: 10.1111/J.1432-0436.1984.TB00265.X

Abstract: In hepatocyte cultures derived from 15-day-old foetal rats, the appearance of the liver (L) form of pyruvate kinase is blocked when cytosine arabinoside is added on the 2nd day of culture. When added on the 3rd day of culture, the inhibitor of DNA synthesis does not prevent the appearance of the enzyme. If cytosine arabinoside is added on the 2nd day of culture and removed on the 4th day, the enzyme is detected by the 6th day of culture. The specificity of the action of cytosine arabinoside for the L form of pyruvate kinase is in contrast with the lack of effect observed on total protein synthesis and the activity of the embryonic (M2) form of the enzyme.

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Publisher: Springer Science and Business Media LLC

Date: 21-11-2016

DOI: 10.1038/NG.3725

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1074/MCP.M114.046110

Dysregulation of miRNA 181b in the temporal cortex in schizophrenia

Publisher: Oxford University Press (OUP)

Date: 09-01-2008

DOI: 10.1093/HMG/DDN005

Abstract: Analysis of global microRNA (miRNA) expression in postmortem cortical grey matter from the superior temporal gyrus, revealed significant up-regulation of miR-181b expression in schizophrenia. This finding was supported by quantitative real-time RT-PCR analysis of miRNA expression in a cohort of 21 matched pairs of schizophrenia and non-psychiatric controls. The implications of this finding are substantial, as this miRNA is predicted to regulate many target genes with potential significance to the development of schizophrenia. They include the calcium sensor gene visinin-like 1 (VSNL1) and the ionotropic AMPA glutamate receptor subunit (GRIA2), which were found to be down-regulated in the same cortical tissue from the schizophrenia group. Both of these genes were also suppressed in miR-181b transfected cells and shown to contain functional miR-181b miRNA recognition elements by reporter gene assay. This study suggests altered miRNA levels could be a significant factor in the dysregulation of cortical gene expression in schizophrenia.

Genetic polymorphisms and childhood acute lymphoblastic leukemia: GWAS of the ESCALE study (SFCE)

Publisher: Springer Science and Business Media LLC

Date: 04-06-2012

DOI: 10.1038/LEU.2012.148

Dermatologists Warn Nation of Increased Skin Cancer Risk

Publisher: Oxford University Press (OUP)

Date: 18-11-1992

DOI: 10.1093/JNCI/84.22.1696

Abstract: We present the case of a rare hamartomatous condition of the small intestine clinically mimicking inflammatory bowel disease. Disorganised fascicles of smooth muscle derived from both muscularis mucosae and propria, bundles of non-myelinated nerve fibres with groups of abnormal ganglion cells, and haemangiomatous vessels were present within the submucosa of a long segment of small intestine causing subacute obstruction.

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.AJHG.2022.06.012

Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in lynch syndrome

Publisher: BMJ

Date: 19-11-2011

DOI: 10.1136/JMG.2010.079962

Abstract: Recently, six colorectal cancer (CRC) susceptibility loci have been identified, and two single-nucleotide polymorphisms (SNPs)--rs16892766 (8q23.3) and rs3802842 (11q23.1)--from two of these regions have been found to be significantly associated with an increased CRC risk in patients with Lynch syndrome. The objective of this study was to genotype nine SNPs within these six loci to confirm previous findings and investigate whether they act as modifiers of disease risk in patients with Lynch syndrome. The patient cohort consisted of 684 mutation-positive patients with Lynch syndrome from 298 Australian and Polish families. Nine SNPs were genotyped: rs16892766 (8q23.3), rs7014346 and rs6983267 (8q24.21), rs10795668 (10p14), rs3802842 (11q23.1), rs10318 and rs4779584 (15q13.3), and rs4939827 and rs4464148 (18q21.1). The data were analysed to investigate possible associations between the presence of variant alleles and the risk of developing disease. An association between SNP rs3802842 on chromosome 11q23.1 and rs16892766 on chromosome 8q23.3 and the risk of developing CRC and age of diagnosis was found in MLH1 mutation carriers. Female MLH1 mutation carriers harbouring the homozygous variant genotype for SNP rs3802842 have the highest risk of developing CRC. When the number of risk alleles for the two SNPs combined was analysed, a difference of 24 years was detected between in iduals carrying three risk alleles and those carrying no risk alleles. The authors were able to replicate the association between the CRC susceptibility loci on chromosomes 8q23.3 and 11q23 and the risk of developing CRC in patients with Lynch syndrome, but the association could only be detected in MLH1 mutation carriers in this study.

Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35

Publisher: Elsevier BV

Date: 08-2004

DOI: 10.1086/422475

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Publisher: Oxford University Press (OUP)

Date: 02-05-2020

DOI: 10.1093/JNCI/DJAA056

Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by in idual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development

Publisher: Cold Spring Harbor Laboratory

Date: 21-11-2017

DOI: 10.1101/222596

Abstract: Transcriptomic imputation approaches offer an opportunity to test associations between disease and gene expression in otherwise inaccessible tissues, such as brain, by combining eQTL reference panels with large-scale genotype data. These genic associations could elucidate signals in complex GWAS loci and may disentangle the role of different tissues in disease development. Here, we use the largest eQTL reference panel for the dorso-lateral pre-frontal cortex (DLPFC), collected by the CommonMind Consortium, to create a set of gene expression predictors and demonstrate their utility. We applied these predictors to 40,299 schizophrenia cases and 65,264 matched controls, constituting the largest transcriptomic imputation study of schizophrenia to date. We also computed predicted gene expression levels for 12 additional brain regions, using publicly available predictor models from GTEx. We identified 413 genic associations across 13 brain regions. Stepwise conditioning across the genes and tissues identified 71 associated genes (67 outside the MHC), with the majority of associations found in the DLPFC, and of which 14/67 genes did not fall within previously genome-wide significant loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple pathways associated with porphyric disorders. We investigated developmental expression patterns for all 67 non-MHC associated genes using BRAINSPAN, and identified groups of genes expressed specifically pre-natally or post-natally.

COGENT (COlorectal cancer GENeTics) revisited

Publisher: Oxford University Press (OUP)

Date: 30-01-2012

DOI: 10.1093/MUTAGE/GER059

The advantages of dense marker sets for linkage analysis with very large families

Publisher: Springer Science and Business Media LLC

Date: 25-01-2007

DOI: 10.1007/S00439-007-0323-5

Abstract: Dense sets of hundreds of thousands of markers have been developed for genome-wide association studies. These marker sets are also beneficial for linkage analysis of large, deep pedigrees containing distantly related cases. It is impossible to analyse jointly all genotypes in large pedigrees using the Lander-Green Algorithm, however, as marker density increases it becomes less crucial to analyse all in iduals' genotypes simultaneously. In this report, an approximate multipoint non-parametric technique is described, where large pedigrees are split into many small pedigrees, each containing just two cases. This technique is demonstrated, using phased data from the International Hapmap Project to simulate sets of 10,000, 50,000 and 250,000 markers, showing that it becomes increasingly accurate as more markers are genotyped. This method allows routine linkage analysis of large families with dense marker sets and represents a more easily applied alternative to Monte Carlo Markov Chain methods.

Heritable DNA methylation marks associated with susceptibility to breast cancer

Publisher: Springer Science and Business Media LLC

Date: 28-02-2018

DOI: 10.1038/S41467-018-03058-6

Abstract: Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA s les provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.

Genome-wide association study identifies novel breast cancer susceptibility loci

Publisher: Springer Science and Business Media LLC

Date: 28-06-2007

DOI: 10.1038/NATURE05887

Differential gene expression and cytokine production from neutrophils in asthma phenotypes

Publisher: European Respiratory Society (ERS)

Date: 24-09-2010

DOI: 10.1183/09031936.00027409

Abstract: Asthma is characterised into eosinophilic and non-eosinophilic phenotypes based on inflammatory cell patterns in airway secretions. Neutrophils are important in innate immunity, and are increased in the airways in non-eosinophilic asthma. The present study investigated the activity of neutrophils in asthma phenotypes. Participants with eosinophilic (n = 8) and non-eosinophilic asthma (n = 9) and healthy controls (n = 11) underwent sputum induction and blood collection. Neutrophils were isolated and cultured with or without lipopolysaccharide. Cytokines were measured by ELISA, and gene expression was analysed using a gene expression microarray and quantitative PCR. In non-eosinophilic asthma, blood neutrophils released significantly higher levels of interleukin-8 at rest. Cytokine gene expression and sputum neutrophil protein production did not differ between asthma subtypes. Microarrays demonstrated closely related expression profiles from participants with non-eosinophilic asthma that were significantly distinct from those in eosinophilic asthma. A total of 317 genes were significantly altered in resting neutrophils from participants with non-eosinophilic asthma versus eosinophilic asthma, including genes related to cell motility and regulation of apoptosis. Non-eosinophilic and eosinophilic asthma are associated with specific gene expression profiles, providing further evidence that these phenotypes of asthma involve different molecular mechanisms of disease pathogenesis at the systemic level. The mechanisms of non-eosinophilic asthma may involve enhancement of blood neutrophil chemotaxis and survival.

A comparison of ten polygenic score methods for psychiatric disorders applied across multiple cohorts

Publisher: Cold Spring Harbor Laboratory

Date: 11-09-2020

DOI: 10.1101/2020.09.10.20192310

Abstract: Polygenic scores (PGSs), which assess the genetic risk of in iduals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies (GWASs). PGS methods differ in which DNA variants are included and the weights assigned to them some require an independent tuning s le to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. The Psychiatric Genomics Consortium working groups for schizophrenia (SCZ) and major depressive disorder (MDD) bring together many independently collected case- control cohorts. We used these resources (31K SCZ cases, 41K controls 248K MDD cases, 563K controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and nine methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) are compared. Compared to PC+T, the other nine methods give higher prediction statistics, MegaPRS, LDPred2 and SBayesR significantly so, up to 9.2% variance in liability for SCZ across 30 target cohorts, an increase of 44%. For MDD across 26 target cohorts these statistics were 3.5% and 59%, respectively. Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparison and are recommended in applications to psychiatric disorders.

BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer

Publisher: Springer Science and Business Media LLC

Date: 16-03-2011

DOI: 10.1007/S10549-011-1443-0

Abstract: Mutations in the recognized breast cancer susceptibility genes BRCA1, BRCA2, TP53, ATM, and CHEK2 account for approximately 20% of hereditary breast cancer. This raises the possibility that mutations in other biologically relevant genes may be involved in genetic predisposition to breast cancer. In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously being associated with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2. Two truncating mutations in PALB2 (Q66X and W1038X), one of which is has not been reported before, were detected in an independent Australian cohort of 70 in iduals with breast or ovarian cancer, and have strong family histories of breast or breast/ovarian cancer. In addition, six missense variants predicted to be causative were detected, one in BRIP1 and five in PALB2. No causative variants were identified in RAD51C. This study supports recent observations that although rare, PALB2 mutations are present in a small but substantial proportion of inherited breast cancer cases, and indicates that RAD51C at a population level does not account for a substantial number of familial breast cancer cases.

CYP3A7*1C allele

Publisher: Springer Science and Business Media LLC

Date: 26-01-2021

DOI: 10.1038/S41416-020-01185-W

Abstract: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. For pregnanediol-3-glucuronide, there were no genome-wide significant associations for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10 –18 ) in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10 –8 ). The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

Increased DNA methylation of SLFN12 in CD4+ and CD8+ T cells from multiple sclerosis patients

Publisher: Public Library of Science (PLoS)

Date: 31-10-2018

DOI: 10.1371/JOURNAL.PONE.0206511

Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report

Publisher: Springer Science and Business Media LLC

Date: 14-10-2019

DOI: 10.1186/S13053-019-0127-3

Abstract: We previously reported that in pathogenic mismatch repair ( path_MMR ) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1 , 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within 1.5, 1.5–2.5, 2.5–3.5 and at 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5–3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively ( p 0.001). Ten-year crude survival when the last colonoscopy had been 1.5, 1.5–2.5, 2.5–3.5 or 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively ( p = 0.91). In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.

Predicting type 2 diabetes using genetic and environmental risk factors in a multi-ethnic Malaysian cohort

Publisher: Elsevier BV

Date: 08-2017

DOI: 10.1016/J.PUHE.2017.04.003

Abstract: Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene-environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene-environment interactions that may explain additional risk variation. This was a case-control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R The models including environmental risk factors only had pseudo R This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene-environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger s les for detection.

Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population

Publisher: Springer Science and Business Media LLC

Date: 04-09-2020

DOI: 10.1007/S12282-020-01151-7

Abstract: The objective of this study was to determine spectrum and prevalence of germline mutations in TP53 gene among Polish women with early-onset breast cancer (BC), which has not been determined until now. A cohort of 100 females with BC diagnosed ≤ 30 years of age and with a positive family history of cancer was used as a discovery cohort. 1880 women with BC ≤ 45 years old and a control group of 2000 healthy women were genotyped as a replication phase of this study. Four heterozygous pathogenic missense mutations were detected in a group of 100 patients with early-onset breast cancer. On the basis of software prediction and available literature data, all these variants were defined as pathogenic. None of these TP53 variants were detected among 1880 breast cancer patients and 2000 healthy controls. No large mutations were found among early-onset cases using MLPA reaction. Germline pathogenic TP53 variants were found in 4% early-onset Polish BC patients. No founder mutations were identified in Polish population. To improve the treatment and surveillance screening, the search for germline TP53 pathogenic variants is recommended for all female BC cases diagnosed ≤ 30 years old.

The RAD51 135 G>C polymorphism modifies breast cancer and ovarian cancer risk in Polish BRCA1 mutation carriers

Publisher: American Association for Cancer Research (AACR)

Date: 02-2007

DOI: 10.1158/1055-9965.EPI-06-0562

Abstract: Breast and ovarian cancer penetrance in BRCA1 mutation carriers is estimated to be between 15% and 80% by age 70 years. At present, it is not possible to predict with any certainty who is most likely to develop disease or which age it will develop. Previous studies have tried to correlate the sites of BRCA1 mutations with disease risk however, the results have not yielded any definitive association. An alternative explanation that could account for differences in the penetrance of BRCA1 mutations is the action of modifier genes. In this study, we have investigated the role of the RAD51_135_G& C polymorphism in breast and ovarian cancer case-control populations of Polish women who have been matched for BRCA1 mutation and year of birth. The results reveal that women who harbor the C allele have almost twice the reduction in breast and ovarian cancer risk compared with women who harbor only the G allele. These findings suggest that the effect of the RAD51 C allele is an important risk modifier for malignancies occurring on a background of BRCA1 mutations. In addition, we were able to show that the site of the BRCA1 mutation does not influence the effect of the RAD51 C allele, indicating that this polymorphism contributes to prevention of disease in BRCA1 carriers. In conclusion, the RAD51 C allele seems to protect against both breast and ovarian cancer in women harboring BRCA1 mutations. (Cancer Epidemiol Biomarkers Prev 2007 (2):270–5)

Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli

Publisher: No publisher found

Date: 1996

DOI: 10.1007/S004390050293

Abstract: Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps predominantly in the colorectal region. Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for most cases of FAP. Mutations at the 5' end of APC are known to be associated with a relatively mild form of the disease, called attenuated adenomatous polyposis coli (AAPC). We identified a frameshift mutation in the 3' part of exon 15, resulting in a stop codon at 1862, in a large Dutch kindred with AAPC. Western blot analysis of lymphoblastoid cell lines derived from affected family members from this kindred, as well as from a previously reported Swiss family carrying a frameshift mutation at codon 1987 and displaying a similar attenuated phenotype, showed only the wild-type APC protein. Our study indicates that chain-terminating mutations located in the 3' part of APC do not result in detectable truncated polypeptides and we hypothesize that this is likely to be the basis for the observed AAPC phenotype.

Constitutional variants in POT1, TERF2IP, and ACD genes in patients with melanoma in the Polish population

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 24-09-2020

DOI: 10.1097/CEJ.0000000000000633

Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Publisher: Wiley

Date: 02-04-2018

DOI: 10.1002/CAM4.1445

Abstract: Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation ( r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy ( P = 6.0 × 10 −3 ) and concordance in effect direction ( P = 2.0 × 10 −3 ) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level ( P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Publisher: Elsevier BV

Date: 11-2020

DOI: 10.1016/J.AJHG.2020.09.001

Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer

Publisher: Wiley

Date: 20-11-2008

DOI: 10.1002/IJC.23177

Abstract: Polymorphisms in the 2 cell-cycle control genes Aurora A and Cyclin D1 have previously been associated with changes in the age of onset of colorectal cancer in persons harboring germline mutations in DNA mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). In this report, we have genotyped 312 in iduals, who all harbored confirmed causative mutations in either hMSH2 or hMLH1, for 2 polymorphisms, one in Aurora A (T91A) and the other in Cyclin D1 (G870A). The results reveal that the previous association with the Aurora A polymorphism could not be confirmed in our larger group of HNPCC patients. The Cyclin D1 polymorphism, however, was associated with a significant difference in the age of disease onset on patients harboring hMSH2 mutations, which was not observed in hMLH1 mutation carriers. A combined analysis of the Aurora A and Cyclin D1 polymorphisms did not reveal any obvious association. In conclusion, it appears that the polymorphic variant of Aurora A does not appear to be associated with variation in colorectal cancer risk in HNPCC, whereas there is a more complex relationship between the Cyclin D1 polymorphism and disease risk in HNPCC.

Deletion mutations in an Australian series of HNPCC patients

Publisher: Springer Science and Business Media LLC

Date: 2005

DOI: 10.1186/1897-4287-3-1-43

Bilateral dysgerminoma associated with gonadoblastoma and sex-cord stromal tumour with annular tubules in a 28-year-old fertile woman with normal karyotype

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1097/PAT.0B013E32835140A5

Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Publisher: Public Library of Science (PLoS)

Date: 13-10-2014

DOI: 10.1371/JOURNAL.PONE.0110255

Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Publisher: Springer Science and Business Media LLC

Date: 14-05-2021

DOI: 10.1038/S41467-021-23162-4

Abstract: A Correction to this paper has been published: 0.1038/s41467-021-23162-4

Do common genotypes of FK506 binding protein 5 (FKBP5) moderate the effects of childhood maltreatment on cognition in schizophrenia and healthy controls?

Publisher: Elsevier BV

Date: 11-2015

DOI: 10.1016/J.JPSYCHIRES.2015.07.019

Abstract: Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total s le of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed' cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment) in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic s les, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration).

Thyroid cancer in a patient with lynch syndrome – case report and literature review

Publisher: Informa UK Limited

Date: 07-2017

DOI: 10.2147/TCRM.S121812

Parental prenatal smoking and risk of childhood acute lymphoblastic leukemia

Publisher: Oxford University Press (OUP)

Date: 05-12-2012

DOI: 10.1093/AJE/KWR275

Abstract: The association between parental smoking and risk of childhood acute lymphoblastic leukemia (ALL) was investigated in an Australian population-based case-control study that included 388 cases and 868 controls aged <15 years, recruited from 2003 to 2006. Both of the child's parents provided information about their smoking habits for each year from age 15 years to the child's birth. Data were analyzed by logistic regression. Maternal smoking was not associated with risk of childhood ALL, but the odds ratio for paternal smoking of ≥15 cigarettes per day around the time of the child's conception was 1.35 (95% confidence interval: 0.98, 1.86). The associations between parental smoking risk of childhood ALL did not differ substantially by immunophenotypic or cytogenetic subtype. Meta-analyses of paternal smoking, including results from the Australian Study of Causes of Acute Lymphoblastic Leukemia in Children and those of previous studies, produced summary odds ratios of 1.15 (95% confidence interval: 1.06, 1.24) for any paternal smoking around the time of the child's conception and 1.44 (95% confidence interval: 1.24, 1.68) for smoking ≥20 cigarettes per day at that time. Study results suggest that heavier paternal smoking around the time of conception is a risk factor for childhood ALL. Men should be strongly encouraged to cease smoking, particularly when planning to start a family.

Inflammatory subtypes in asthma: Assessment and identification using induced sputum

Publisher: Wiley

Date: 2006

DOI: 10.1111/J.1440-1843.2006.00784.X

Abstract: The authors sought to investigate the detection of non-eosinophilic asthma using induced sputum. Although this is an important subtype of clinical asthma, its recognition is not standardized. Adult non-smokers with asthma and healthy controls underwent sputum induction and hypertonic saline challenge. Non-eosinophilic asthma was defined as symptomatic asthma with normal sputum eosinophil counts. The normal range for sputum eosinophil count was determined using the 95th percentile from the healthy control group as a cut-off point. The recognition of non-eosinophilic asthma using eosinophil proportion was in agreement with a definition based on absolute eosinophil count (kappa 0.67). Non-eosinophilic asthma was a stable subtype over both the short term (4 weeks) and longer term (5 years, kappa 0.77). Airway inflammation in asthma could be categorized into four inflammatory subtypes based on sputum eosinophil and neutrophil proportions. These subtypes were neutrophilic asthma, eosinophilic asthma, mixed granulocytic asthma and paucigranulocytic asthma. Subjects with increased neutrophils (neutrophilic asthma and mixed granulocytic asthma) were older and had an increased total cell count and cell viability compared with other subtypes. Induced sputum eosinophil proportion is a good discriminator for eosinophilic asthma, providing a reproducible definition of a homogenous group. The remaining non-eosinophilic subjects are heterogeneous and can be further classified based on the presence of neutrophils. These inflammatory subtypes have important implications for the investigation and characterization of airway inflammation in asthma.

A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes

Publisher: Springer Science and Business Media LLC

Date: 24-06-2011

DOI: 10.1186/1471-2407-11-265

Abstract: Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify licons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical lification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the licon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the licons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of s les enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to in iduals who currently do not undergo mutation testing because of the significant costs involved.

Serum 25(OH)D concentration, common variants of the VDR gene and lung cancer occurrence

Publisher: Wiley

Date: 24-04-2017

DOI: 10.1002/IJC.30740

Abstract: The first aim of our study was to examine the association between common variants in VDR [rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI) and rs11568820 (Cdx2)] and lung cancer risk in the Polish population. Genotyping and statistical analysis which included Chi-square test with Yates correction and haplotype frequency analysis were performed on a series of 840 consecutively collected lung cancer patients and 920 healthy controls. The second aim was to evaluate the link between serum 25(OH)D concentration and the number of lung cancers in a subgroup of 200 patients. A separate control group that consisted of 400 matched (by age, sex, smoking habits and the season of blood collection) healthy in iduals was used to avoid posterior adjustment on the matched variables. Statistical analysis with the use of Chi-square test with Yates was performed. We found no statistically significant difference in the distribution of the allels of studied VDR variants among cases and controls. A statistically significant over-representation of VDR haplotypes: rs731236_A + rs1544410_T [odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.11-5.32, p < 0.001], rs731236_G + rs1544410_T (OR = 1.54, 95% CI = 1.31-1.81, p < 0.001) and rs731236_G + rs1544410_C (OR = 0.04, 95% CI = 0.03-0.07, p < 0.001) was detected. We found a tendency toward an increased number of lung cancers among in iduals with low serum levels of 25(OH)D. To answer the question, whether VDR can be regarded as lung cancer susceptibility gene and low 25(OH)D serum levels is associated with lung cancer occurrences, additional, multicenter study needs to be performed.

Exposure to household paintyng and floor treatments, and parental occupational paint exposure and risk of childhood brain tumors: Results from an Australia case-control study

Publisher: Springer Science and Business Media LLC

Date: 12-12-2014

DOI: 10.1007/S10552-013-0330-X

Abstract: Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. This study investigated whether household exposure to paints and floor treatments and parental occupational painting were associated with CBT risk in a population-based case-control study conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing, frequency matched to cases on age, sex, and state of residence. Data were obtained from parents in mailed questionnaires and telephone interviews. Information on domestic painting and floor treatments, and parental occupational exposure to paint, in key periods relating to the index pregnancy and childhood was obtained for 306 cases and 950 controls. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders. Overall, we found little evidence that parental, fetal, or childhood exposure to home painting or floor treatments was associated with risk of CBT. There was, though, some evidence of a positive association between childhood exposure to indoor painting and risk of high-grade glioma [odds ratio (OR) 3.31, 95 % confidence interval (CI) 1.29, 8.52] based on very small numbers. The OR for the association between CBT and paternal occupational exposure to paint any time before the pregnancy was 1.32 (95 % CI 0.90, 1.92), which is consistent with the results of other studies. Overall, we found little evidence of associations between household exposure to paint and the risk of CBT in any of the time periods investigated.

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Publisher: Springer Science and Business Media LLC

Date: 17-11-2009

DOI: 10.1038/SJ.BJC.6605338

MicroRNA-16 Is Down-Regulated in Mutated FLT3 Expressing Murine Myeloid FDC-P1 Cells and Interacts with Pim-1

Publisher: Public Library of Science (PLoS)

Date: 06-09-2012

DOI: 10.1371/JOURNAL.PONE.0044546

Contribution of large genomic rearrangements inPALB2to familial breast cancer: implications for genetic testing

Publisher: BMJ

Date: 08-04-2023

DOI: 10.1136/JMEDGENET-2021-108399

Abstract: PALB2 is the most important contributor to familial breast cancer after BRCA1 and BRCA2 . Large genomic rearrangements (LGRs) in BRCA1 and BRCA2 are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs in PALB2 has not been systematically studied. We performed targeted sequencing and real-time qPCR validation to identify LGRs in PALB2 in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population. Seven large deletions ranging in size from 0.96 kbp to 18.07 kbp involving PALB2 were identified in seven cases, while no LGRs were identified in any of the controls. Six LGRs were considered pathogenic as they included one or more exons of PALB2 and disrupted the WD40 domain at the C terminal end of the PALB2 protein while one LGR only involved a partial region of intron 10 and was considered a variant of unknown significance. Altogether, pathogenic LGRs identified in this study accounted for 10.3% (6 of 58) of the pathogenic PALB2 variants detected among the 5770 families with familial breast cancer. Our data show that a clinically important proportion of PALB2 pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion of PALB2 LGRs in routine clinical genetic testing.

Biological insights from 108 schizophrenia-associated genetic loci

Publisher: Springer Science and Business Media LLC

Date: 07-2014

DOI: 10.1038/NATURE13595

High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile

Publisher: Springer Science and Business Media LLC

Date: 16-08-2022

DOI: 10.1007/S11357-022-00643-Y

Abstract: Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an in idual’s polygenic risk score (PRS) for EL. We tested the hypothesis that in iduals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) ( n = 407,800, 40–69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study ( n = 2122, 55–85 years), Older Australian Twins Study ( n = 539, 65–90 years) and Sydney Memory and Ageing Study ( n = 925, 70–90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies ( n = 2273, 70–93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22–30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 × 10 –42 ) and its components ( p 2.30 × 10 – 8 ). Meta-analyses of the replication cohorts showed nominal associations with MetS ( p = 0.028) and 3 MetS components ( p 0.05). This work suggests in iduals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity.

Erythrocyte microRNA sequencing reveals differential expression in relapsing-remitting multiple sclerosis

Publisher: Springer Science and Business Media LLC

Date: 21-05-2018

DOI: 10.1186/S12920-018-0365-7

BRCA1 mutations found in archived early onset breast tumours

Publisher: Elsevier BV

Date: 04-1997

DOI: 10.1016/S0959-8049(96)00499-6

Abstract: Inherited mutations in the BRCA1 gene are thought to account for approximately 5% of breast cancers in women under the age of 45 years. In order to determine whether mutations could be found at the expected frequency, 60% of the protein coding region of BRCA1 was screened in 75 archived early-onset breast tumours, taken from women under 45 years of age. Two of the 75 tumours (2.7%) had detectable mutations, in close agreement to that predicted. Since BRCA1 mutations found in breast tumours are invariably germline, two immediate consequences are apparent. Firstly, family members of affected patients are likely to carry mutations as well, and should be considered for BRCA1 screening and secondly, persons harbouring a germline BRCA1 mutation should be examined frequently and indefinitely for new primary tumours in remaining breast tissue.

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

Publisher: Springer Science and Business Media LLC

Date: 23-12-2012

DOI: 10.1038/NG.2500

Relative frequency and morphology of cancers in STK11 mutation carriers

Publisher: Elsevier BV

Date: 06-2004

DOI: 10.1053/J.GASTRO.2004.03.014

Abstract: There is limited data on the spectrum and risk for cancer associated with germline serine/threonine protein kinase 11 (STK11) mutations that cause Peutz-Jeghers syndrome (PJS). We analyzed the incidence of cancer in 240 in iduals with PJS possessing germline mutations in STK11. Fifty-four cancers were found among carriers. Overall, the risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 1%, 3%, 19%, 32%, 63%, and 81%, respectively. Kaplan-Meier analysis showed similar cancer risks between missense and truncating mutation carriers (log-rank chi(2) = 2.48 P = 0.12). There was some evidence that mutations in exon 3 of STK11 were associated with a higher cancer risk than mutations within other regions of the gene. We found no difference in overall cancer risk between male and female carriers (log-rank chi(2) = 1.31 P = 0.25) or between familial and sporadic cases (log-rank chi(2) = 1.16, with 1 df P = 0.28). The most common cancers represented were gastrointestinal in origin--gastroesophageal, small bowel, colorectal, and pancreatic--and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 10%, 18%, and 42%, respectively. In women, the risk for breast cancer was substantially increased, being 32% by age 60 years. These results quantitatively show the spectrum of cancer risk associated with STK11 germline mutations in the context of PJS and provide a valuable reference for defining surveillance regimens.

How Common is Hereditary Cancer?

Publisher: Informa UK Limited

Date: 1994

DOI: 10.3109/07853899409147886

Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Publisher: Springer Science and Business Media LLC

Date: 22-09-2014

DOI: 10.1038/NCOMMS5883

Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 in iduals of European ancestry and 6,784 in iduals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

BRCA1/2 mutations are not a common cause of malignant melanoma in the Polish population

Publisher: Public Library of Science (PLoS)

Date: 04-10-2018

DOI: 10.1371/JOURNAL.PONE.0204768

Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.JACI.2013.12.1091

Abstract: Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC) carboxypeptidase A3 (CPA3) deoxyribonuclease I-like 3 (DNASE1L3) IL-1β (IL1B) alkaline phosphatase, tissue-nonspecific isozyme (ALPL) and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P 12% change in FEV1 AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Publisher: Springer Science and Business Media LLC

Date: 30-07-2018

DOI: 10.1038/S41467-018-05369-0

Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 in iduals of European ( N = 60,552), African ( N = 8429), Asian ( N = 9959), and Hispanic/Latino ( N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12 . Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

Publisher: Informa UK Limited

Date: 12-2021

DOI: 10.2147/PGPM.S337147

The VEGF_936_C>T 3'UTR polymorphism reduces BRCA1-associated breast cancer risk in Polish women.

Publisher: Elsevier BV

Date: 04-2008

DOI: 10.1016/J.CANLET.2007.11.029

Abstract: The vascular endothelial growth factor (VEGF) plays a crucial role in the initiation of angiogenesis, which is an important stage in tumor development. A functional 936_C>T polymorphism in the VEGF gene and its association with sporadic breast cancer risk has been analyzed in various studies yielding conflicting results. To analyze the role of this polymorphism in modifying hereditary breast and ovarian cancer risks, we conducted a case-control study and genotyped 755 Polish BRCA1 carriers, including 319 breast cancer cases, 146 ovarian cancer cases, and 290 unaffected controls. The results revealed an association of the CT+TT genotypes with a reduced breast cancer risk (OR(adj) 0.63, 95% CI, 0.41-0.98 OR(clustered) 0.63, 95% CI, 0.48-0.83), and a potential effect on ovarian cancer risk (OR(adj) 0.62, 95% CI, 0.33-1.18 OR(clustered) 0.62, 95% CI, 0.47-0.83). Thus, the 936_C>T polymorphism appears to modify disease risks in BRCA1 carriers.

Temozolomide induces senescence but not apoptosis in human melanoma cells

Publisher: Springer Science and Business Media LLC

Date: 30-10-2007

DOI: 10.1038/SJ.BJC.6604017

Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi‐ethnic cohort

Publisher: Wiley

Date: 24-03-2015

DOI: 10.1111/DME.12735

Abstract: To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. After Bonferroni correction, seven in idual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian s le. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations.

Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation

Publisher: Elsevier BV

Date: 04-2013

DOI: 10.1016/J.NEUROSCIENCE.2013.01.014

Abstract: Iron abnormalities within the brain are associated with several rare but severe neurodegenerative conditions. There is growing evidence that more common systemic iron loading disorders such as hemochromatosis can also have important effects on the brain. To identify features that are common across different forms of hemochromatosis, we used microarray and real-time reverse transcription polymerase chain reaction (RT-PCR) to assess brain transcriptome profiles of transferrin receptor 2 mutant mice (Tfr2(mut)), a model of a rare type of hereditary hemochromatosis, relative to wildtype control mice. The results were compared with our previous findings in dietary iron-supplemented wildtype mice and Hfe(-/-) mice, a model of a common type of hereditary hemochromatosis. For transcripts showing significant changes relative to controls across all three models, there was perfect (100%) directional concordance (i.e. transcripts were increased in all models or decreased in all models). Comparison of the two models of hereditary hemochromatosis, which showed more pronounced changes than the dietary iron-supplemented mice, revealed numerous common molecular effects. Pathway analyses highlighted changes for genes relating to long-term depression (6.8-fold enrichment, p=5.4×10(-7)) and, to a lesser extent, long-term potentiation (3.7-fold enrichment, p=0.01), with generalized reductions in transcription of key genes from these pathways, which are involved in modulating synaptic strength and efficacy and are essential for memory and learning. The agreement across the models suggests the findings are robust and strengthens previous evidence that iron loading disorders affect the brain. Perturbations of brain phenomena such as long-term depression and long-term potentiation might partly explain neurologic symptoms reported for some hemochromatosis patients.

Association between early-onset breast and laryngeal cancers

Publisher: Springer Science and Business Media LLC

Date: 06-12-2006

DOI: 10.1007/S10549-005-9116-5

Abstract: Recent studies suggest that there are groups of genes that predispose simultaneously to both early-onset breast and laryngeal cancer. Studies were performed on a large series of unselected patients with laryngeal cancer diagnosed in Szczecin, Poland. Pedigrees of 683 laryngeal cancer patients were analysed for the frequency of early-onset and late-onset breast cancer among first degree relatives. The observed frequencies of breast cancer in these families were compared to those expected. In addition, common mutations/variants in the 3 genes BRCA1, NOD2 and CYP1B1, known to be associated with early-onset breast cancer, were assessed to determine their frequency in 348 unselected laryngeal cancers. The average age at diagnosis of LC among patients, who had relatives affected by BC diagnosed under the age of 50 years was 57.62. In comparison LC patients reporting a first degree relative affected by BC diagnosed above 50 years of age, had an average age of diagnosis of 66.00 years, which was significantly different (p=0.0064). Similarly, the average age of diagnosis of BC among patients with LC diagnosed under age of 50 years was 46.7 years and whereas LC patients with tumors diagnosed above 50 years had relatives diagnosed with breast cancer at an average age of 53.37 years, which was significantly different (p=0.02). From the 348 consecutive ascertained laryngeal cancer patients who had molecular studies undertaken, breast cancers among first degree relatives were found in 18 families including 8 with breast cancers diagnosed less than 50 years of age. A molecular basis was identified (the CYP1B1 355T/T genotype) in only 2 of the 8 early cases suggestive of there being additional, as yet unknown genes that are associated with an early-onset laryngeal-breast cancer phenotype.

Mind Over Matter: Confronting Challenges in Post-Mortem Brain Biobanking for Glioblastoma Multiforme

Publisher: SAGE Publications

Date: 2021

DOI: 10.1177/11772719211013359

Abstract: Over the past 10 years, there has been limited progress for the treatment of brain cancer and outcomes for patients are not much improved. For brain cancer researchers, a major obstacle to biomarker driven research is limited access to brain cancer tissue for research purposes. The Mark Hughes Foundation Brain Biobank is one of the first post-mortem adult brain banks in Australia to operate with protocols specifically developed for brain cancer. Located within the Hunter New England Local Health District and operated by Hunter Cancer Biobank, the boundaries of service provided by the Brain Bank extend well into the surrounding regional and rural areas of the Local Health District and beyond. Brain cancer biobanking is challenging. There are conflicting international guidelines for best practice and unanswered questions relating to scientific, psychosocial and operational practices. To address this challenge, a best practice model was developed, informed by a consensus of existing data but with consideration of the difficulties associated with operating in regional or resource poor settings. The regional application of this model was challenged following the presentation of a donor located in a remote area, 380km away from the biobank. This required biobank staff to overcome numerous obstacles including long distance patient transport, lack of palliative care staff, death in the home and limited rural outreach services. Through the establishment of shared goals, contingency planning and the development of an informal infrastructure, the donation was facilitated within the required timeframe. This experience demonstrates the importance of collaboration and networking to overcome resource insufficiency and geographical challenges in rural cancer research programmes.

Closing the case of APOE in multiple sclerosis: No association with disease risk in over 29 000 subjects

Publisher: BMJ

Date: 09-2012

DOI: 10.1136/JMEDGENET-2012-101175

Abstract: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Given the large s le size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

Common variants of DNA repair genes and malignant melanoma

Publisher: Elsevier BV

Date: 2008

DOI: 10.1016/J.EJCA.2007.10.006

Abstract: In the current study, we evaluated the possible associations of seven common variants of the DNA repair and cell cycle control genes BRCA2 and CHEK2 with malignant melanoma (MM). We genotyped 630 unselected MM patients and over 3700 controls (newborns, age- and sex-matched healthy adults with negative cancer family histories, and the adults selected at random by family doctors) for the prevalence of three common variants of the BRCA2 (T1915M, N991D and N372H) and four common variants of the CHEK2 (1100delC, VS2+1G --> A, I157T and del5395). Our study strongly suggests that the common variant of the BRCA2 gene -- the N991D variant is associated with malignant melanoma risk (OR=1.8, p=0.002 after Bonferroni correction). Patients homozygote for the N991D variant were present in 0.32% of cases and only 0.13% of controls. The other variants studied were not over-represented among MM patients when compared to the general population. In conclusion, we report an increased melanoma risk among carriers of the N991D change of the BRCA2 and no association of the CHEK2 changes with malignant melanoma.

Familial association of laryngeal, lung, stomach and early-onset breast cancer

Publisher: Springer Science and Business Media LLC

Date: 21-12-2008

DOI: 10.1007/S10549-007-9869-0

Abstract: This study analyzes the incidence of different types of cancer among 2839 first-degree relatives of 760 consecutive, unselected laryngeal cancer patients, compared with the general population. A statistically significant excess was seen for other cancers of the larynx (SIR: 400), lung (SIR: 135) and stomach (SIR: 271), and early-onset breast cancer (SIR: 287). Familial laryngeal cancer may not be a single site-specific cancer syndrome.

Gastrointestinal polyps in McCune Albright syndrome

Publisher: BMJ

Date: 28-02-2011

DOI: 10.1136/JMG.2010.086330

Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz–Jeghers syndrome patients

Publisher: Wiley

Date: 10-2002

DOI: 10.1034/J.1399-0004.2002.620405.X

Abstract: Peutz-Jeghers syndrome (PJS) is a rare cancer predisposition, which is characterized by the presence of hamartomatous polyposis and mucocutaneous pigmentation. A significant proportion of both familial and sporadic forms of this disorder are associated with mutations in the STK11 (serine/threonine kinase 11)/LKB1 gene. In this report we present a series of Australian PJS cases, which suggest that mutations in the STK11 gene do not account for many families or patients without a family history. The most likely explanation is either the presence of another susceptibility gene or genetic mosaicism in the non-familial patients.

Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?

Publisher: Wiley

Date: 23-06-2011

DOI: 10.1111/J.1399-0004.2010.01489.X

Abstract: Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor (MITF), Pax3, Sox10, SNAI2 ] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed.

Multi-tissue transcriptome-wide association study identifies eight candidate genes and tissue-specific gene expression underlying endometrial cancer susceptibility

Publisher: Springer Science and Business Media LLC

Date: 21-10-2021

DOI: 10.1038/S42003-021-02745-3

Abstract: Genome-wide association studies (GWAS) have revealed sixteen risk loci for endoemtrial cancer but the identification of candidate susceptibility genes remains challenging. Here, we perform transcriptome-wide association study (TWAS) analyses using the largest endometrial cancer GWAS and gene expression from six relevant tissues, prioritizing eight candidate endometrial cancer susceptibility genes, one of which ( EEFSEC ) is located at a potentially novel endometrial cancer risk locus. We also show evidence of biologically relevant tissue-specific expression associations for CYP19A1 (adipose), HEY2 (ovary) and SKAP1 (whole blood). A phenome-wide association study demonstrates associations of candidate susceptibility genes with anthropometric, cardiovascular, diabetes, bone health and sex hormone traits that are related to endometrial cancer risk factors. Lastly, analysis of TWAS data highlights candidate compounds for endometrial cancer repurposing. In summary, this study reveals endometrial cancer susceptibility genes, including those with evidence of tissue specificity, providing insights into endometrial cancer aetiology and avenues for therapeutic development.

Cohort profile: The hunter community study

Publisher: Oxford University Press (OUP)

Date: 07-01-2010

DOI: 10.1093/IJE/DYP343

Demethylation by 5-aza-2'-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists

Publisher: Springer Science and Business Media LLC

Date: 12-07-2010

DOI: 10.1186/1471-2407-10-366

Abstract: DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. Aberrant epigenetic gene silencing in tumours is a frequent event, yet the factors which dictate which genes are targeted for inactivation are unknown. DNA methylation and histone acetylation can be modified with the chemical agents 5-aza-2'-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) respectively. The aim of this study was to analyse de-methylation and re-methylation and its affect on gene expression in colorectal cancer cell lines treated with 5-aza-dC alone and in combination with TSA. We also sought to identify methylation patterns associated with long term reactivation of previously silenced genes. Colorectal cancer cell lines were treated with 5-aza-dC, with and without TSA, to analyse global methylation decreases by High Performance Liquid Chromatography (HPLC). Re-methylation was observed with removal of drug treatments. Expression arrays identified silenced genes with differing patterns of expression after treatment, such as short term reactivation or long term reactivation. Sodium bisulfite sequencing was performed on the CpG island associated with these genes and expression was verified with real time PCR. Treatment with 5-aza-dC was found to affect genomic methylation and to a lesser extent gene specific methylation. Reactivated genes which remained expressed 10 days post 5-aza-dC treatment featured hypomethylated CpG sites adjacent to the transcription start site (TSS). In contrast, genes with uniformly hypermethylated CpG islands were only temporarily reactivated. These results imply that 5-aza-dC induces strong de-methylation of the genome and initiates reactivation of transcriptionally inactive genes, but this does not require gene associated CpG island de-methylation to occur. In addition, for three of our selected genes, hypomethylation at the TSS of an epigenetically silenced gene is associated with the long term reversion of gene expression level brought about by alterations in the epigenetic status following 5-aza-dC treatment.

Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease – A Systematic Review

Publisher: Frontiers Media SA

Date: 22-12-2021

DOI: 10.3389/FIMMU.2021.790803

Abstract: Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn’s disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.

Multiethnic meta-analysis identifies new loci for pulmonary function

Publisher: Cold Spring Harbor Laboratory

Date: 05-10-2017

DOI: 10.1101/196048

Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 in iduals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

Preliminary evidence of an interaction between the FOXP2 gene and childhood emotional abuse predicting likelihood of auditory verbal hallucinations in schizophrenia

Publisher: Elsevier BV

Date: 03-2014

DOI: 10.1016/J.JPSYCHIRES.2013.11.012

Abstract: The FOXP2 gene is involved in the development of speech and language. As some single nucleotide polymorphisms (SNPs) of FOXP2 have been found to be associated with auditory verbal hallucinations (AVHs) at trend levels, this study set out to undertake the first examination into whether interactions between candidate FOXP2 SNPs and environmental factors (specifically, child abuse) predict the likelihood of AVHs. Data on parental child abuse and FOXP2 SNPs previously linked to AVHs (rs1456031, rs2396753, rs2253478) were obtained from the Australian Schizophrenia Research Bank for people with schizophrenia-spectrum disorders, both with (n = 211) and without (n = 122) a lifetime history of AVHs. Genotypic frequencies did not differ between the two groups however, logistic regression found that childhood parental emotional abuse (CPEA) interacted with rs1456031 to predict lifetime experience of AVH. CPEA was only associated with significantly higher levels of AVHs in people with CC genotypes (odds ratio = 4.25), yet in the absence of CPEA, people with TT genotypes had significantly higher levels of AVHs than people with CC genotypes (odds ratio = 4.90). This interaction was specific to auditory verbal hallucinations, and did not predict the likelihood of non-verbal auditory hallucinations. Our findings offer tentative evidence that FOXP2 may be a susceptibility gene for AVHs, influencing the probability people experience AVHs in the presence and absence of CPEA. However, these findings are in need of replication in a larger study that addresses the methodological limitations of the present investigation.

Genetic variants linked to education predict longevity

Publisher: Proceedings of the National Academy of Sciences

Date: 31-10-2016

DOI: 10.1073/PNAS.1605334113

Abstract: In iduals with more education tend to live longer. Genetic variants have been discovered that predict educational attainment. We tested whether a “polygenic score” based on these genetic variants could make predictions about people’s lifespan. We used data from three cohort studies (including ,000 participants) to examine the link between offspring polygenic score for education and parental longevity. Across the studies, we found that participants with more education-linked genetic variants had longer-living parents compared with those with the lowest genetic education scores, those with the highest scores had parents who lived on average 6 months longer. This finding suggests the hypothesis that part of the ultimate explanation for the extended longevity of better-educated people is an underlying, quantifiable, genetic propensity.

Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene

Publisher: Elsevier BV

Date: 1994

DOI: 10.1016/0959-8049(94)00294-F

Abstract: In the present study, the polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) technique has been applied to the mutation analysis of the adenomatous polyposis coli (APC) gene. We examined the first 14 exons of the APC gene in 46 polyposis coli patients. Five germline mutations were observed, including a single-nucleotide substitution and small (1-4 bp) deletions leading, in 4 cases, to a stop codon. A missense mutation in exon 3 and a 1 bp deletion in exon 4 of the APC gene were observed in patients presenting with the attenuated form of FAP.

Electro-oculographic and electroretinographic studies in HNPCC gene mutation carriers

Publisher: S. Karger AG

Date: 2003

DOI: 10.1159/000072149

Abstract: i Purpose: /i To assess retinal function in HNPCC gene mutation carriers. i Patients: /i 19 carriers (38 eyes) of HNPCC genes and controls. i Methods: /i Electro-oculogram, standard flash electroretinogram and pattern electroretinogram (PERG) recordings were performed. i Results: /i In the total group of HNPCC gene mutation carriers examined by oscillatory potentials, reduced litude (p 0.0004) and increased latency (p 0.04) of the O3 wave and increased latency (p 0.02) of the O4 wave were found. In the subgroup of carriers with hMLH1 gene mutation, reduced litudes of the O3 (p 0.0005) and O4 (p 0.04) waves were identified. In the total group of HNPCC gene mutation carriers examined by PERG, reduced litudes of the P50 (p 0.003), N95 (p 0.02) and abnormal N95/P50 ratio (p 0.02) were revealed. In the subgroup of hMLH1 gene mutation carriers, reduced litude of the P50 (p 0.04) and abnormal N95/P50 ratio (p 0.02) were observed, whereas in the hMSH2 gene mutation carrier subgroup, reduced litude (p 0.03), shortened latency of the P50 wave (p 0.02) and reduced litude of the N95 wave (p 0.03) were found. i Conclusion: /i Constitutional dysfunction of the inner retina appears to be a characteristic feature of HNPCC gene mutation carriers.

Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks

Publisher: Springer Science and Business Media LLC

Date: 25-10-2007

DOI: 10.1007/S10549-006-9417-3

Abstract: Methylenetetrahydrofolate reductase (MTHFR), a key regulatory enzyme in the metabolism of folate, is suspected to play a role in the etiology of cancer, via its effects on DNA methylation and nucleotide synthesis. In this study we have investigated the effect of two functional polymorphisms of the MTHFR gene, MTHFR_677_C > T and MTHFR_1298_A > C, on breast and ovarian cancer risk in Polish BRCA1 mutation carriers. The study included 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Odds ratios (OR) were calculated using univariate and multivariate logistic regression taking into account a series of confounding variables that potentially could have biased any association. The results revealed that the MTHFR_677_C > T change was associated with an increased risk of breast and ovarian cancer. The MTHFR_1298_A > C polymorphism was only associated with a decrease in breast cancer risk. Together, it appears that functional polymorphisms in the MTHFR gene modify the risk of breast and may potentially alter the risk of ovarian cancer in women with an inherited predisposition.

Copy number variants associated with 18p11.32, DCC and the promoter 1B region of APC in colorectal polyposis patients

Publisher: Elsevier BV

Date: 02-2016

DOI: 10.1016/J.MGENE.2015.12.005

Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer

Publisher: Wiley

Date: 15-06-1999

DOI: 10.1002/(SICI)1097-0142(19990615)85:12<2512::AID-CNCR4>3.0.CO;2-G

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is linked genetically to mutations in DNA mismatch repair (MMR) genes. Because a deficiency in MMR does not predict a specific phenotype, the original selection criteria may be too restrictive in identifying additional families. The current study was performed to determine whether a relaxation of the Amsterdam criteria (AC) could be applied to identify more families associated with DNA MMR. Twenty-eight unrelated Swiss families (15 complying with the AC and 13 fulfilling extended criteria [EC] to include other tumors of the HNPCC spectrum as well) were screened for mutations in the MMR genes hMSH2 and hMLH1, using single-stranded conformation polymorphism and direct DNA sequencing. Microsatellite instability (MSI) was determined in 14 families. A comparison was made between the phenotypic characteristics of the mutation positive and mutation negative families. Ten AC families (67%) harbored germline mutations in hMLH1 (6 kindreds) or hMSH2 (4 kindreds). In none of the EC kindreds could an unambiguous disease-causing mutation be identified. Seven of eight AC families were found to display MSI whereas all colorectal carcinomas (CRC) in eight EC kindreds were MSI stable. CRC patients from mutation positive families had an earlier age at diagnosis (44 years vs. 49 years) and appeared to have a better survival (11.1 years vs. 7.7 years). Extending the AC to include extracolonic tumors of the HNPCC spectrum results in a very low mutation detection rate for hMSH2 and hMLH1. The EC families appear to represent an alternative genetic entity not necessarily related to DNA MMR gene mutations because they do not display MSI.

Epimutations, inheritance and causes of aberrant DNA methylation in cancer

Publisher: Springer Science and Business Media LLC

Date: 2006

DOI: 10.1186/1897-4287-4-2-75

Informed consent and BRCA1 mutation detection in archived breast tumour specimens

Publisher: Elsevier BV

Date: 04-1996

DOI: 10.1016/S0140-6736(96)90647-9

Dupuytren's disease and the risk of malignant neoplasms

Publisher: Springer Science and Business Media LLC

Date: 06-03-2014

DOI: 10.1186/1897-4287-12-6

Expression of renin–angiotensin system (RAS) components in endometrial cancer

Publisher: Bioscientifica

Date: 2017

DOI: 10.1530/EC-16-0082

Abstract: A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium mRNA levels of (pro)renin receptor ( ATP6AP2 ), angiotensin II type 1 receptor ( AGTR1 ), angiotensin-converting enzyme ( ACE1 ) and angiotensin-converting enzyme 2 ( ACE2 ) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium ( P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 ( TGFB1 ), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue ( P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2 , AGTR1 and ACE1 , key elements of the pro-angiogenic roliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.

Late Breaking News: Commission Urges Stronger Leadership Against AIDS

Publisher: Oxford University Press (OUP)

Date: 16-10-1991

DOI: 10.1093/JNCI/83.20.1449

Genome-wide association meta-analysis of functional outcome after ischemic stroke.

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 22-02-2019

DOI: 10.1212/WNL.0000000000007138

Abstract: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0–2 vs 3–6 and 0–1 vs 2–6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p 5 × 10 −8 . We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0–2 vs 3–6, p = 5.3 × 10 −9 ). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21 , which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome ( p 10 −5 ), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4 , TEK , and PTCH1 ). In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Publisher: Cold Spring Harbor Laboratory

Date: 11-10-2017

DOI: 10.1101/198234

Abstract: High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 21-03-2017

DOI: 10.1038/NCOMMS14774

Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique in iduals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6 P =1 × 10 −4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS ( P =8.4 × 10 −7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Lack of association between genetic polymorphisms in cytokine genes and disease expression in patients with hereditary non-polyposis colorectal cancer

Publisher: Informa UK Limited

Date: 2007

DOI: 10.1080/00365520601106699

Abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in DNA mismatch repair (MMR) genes and is characterized by familial aggregations of early-onset epithelial cancers. Inflammatory cells produce an attractive environment for tumour growth since reactive oxygen and nitrogen species generated by inflammatory cytokine induction can cause damage to DNA and proteins. In this study the objective was to investigate single nucleotide polymorphisms (SNPs) in cytokine genes to assess their impact on disease expression in in iduals diagnosed with HNPCC. DNA s les from 220 participants diagnosed with HNPCC were genotyped for SNPs in IL-6, IL-1beta, TNF-alpha, IFN-gamma, IL-10, IL-4 and IL-1RN. The association between the polymorphisms and disease characteristics, i.e. affected or unaffected with colorectal cancer (CRC) and age of diagnosis of CRC, was tested with the Pearson chi2 test and by Kaplan-Meier survival analysis. There was no significant difference between CRC patients and unaffected MMR gene mutation carriers for any of the SNPs studied and the Kaplan-Meier survival analysis showed no significant difference between age of diagnosis of CRC and genotype. The SNPs selected for this study do not appear to modify disease expression in HNPCC. Given the complexity of the inflammatory response, the limited number of SNPs studied does not rule out the notion that other cytokine polymorphisms could act as disease modifiers of disease expression in HNPCC.

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

Publisher: Springer Science and Business Media LLC

Date: 28-02-2019

DOI: 10.1186/S13053-019-0106-8

Sifting the wheat from the chaff: prioritizing GWAS results by identifying consistency across analytical methods

Publisher: Wiley

Date: 28-11-2011

DOI: 10.1002/GEPI.20622

Abstract: The curse of multiple testing has led to the adoption of a stringent Bonferroni threshold for declaring genome-wide statistical significance for any one SNP as standard practice. Although justified in avoiding false positives, this conservative approach has the potential to miss true associations as most studies are drastically underpowered. As an alternative to increasing s le size, we compare results from a typical SNP-by-SNP analysis with three other methods that incorporate regional information in order to boost or d en an otherwise noisy signal: the haplotype method (Schaid et al. [2002] Am J Hum Genet 70:425-434), the gene-based method (Liu et al. [2010] Am J Hum Genet 87:139-145), and a new method (interaction count) that uses genome-wide screening of pairwise SNP interactions. Using a modestly sized case-control study, we conduct a genome-wide association studies (GWAS) of age-related macular degeneration, and find striking agreement across all methods in regions of known associated variants. We also find strong evidence of novel associated variants in two regions (Chromosome 2p25 and Chromosome 10p15) in which the in idual SNP P-values are only suggestive, but where there are very high levels of agreement between all methods. We propose that consistency between different analysis methods may be an alternative to increasingly larger s le sizes in sifting true signals from noise in GWAS.

Virus Infections and Sudden Death in Infancy: The Role of Interferon-γ

Publisher: Frontiers Media SA

Date: 11-03-2015

DOI: 10.3389/FIMMU.2015.00107

Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer

Publisher: Wiley

Date: 14-05-2015

DOI: 10.1016/J.MOLONC.2015.05.001

Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.

Publisher: BMJ

Date: 03-2002

DOI: 10.1136/JMG.39.3.E12

Genetic and environmental modifiers of cancer risk in lynch syndrome

Publisher: Springer International Publishing

Date: 2018

DOI: 10.1007/978-3-319-74259-5_5

Genetic epidemiology studies in hereditary non-polyposis colorectal cancer

Publisher: Humana Press

Date: 2009

DOI: 10.1007/978-1-60327-492-0_4

Abstract: Genetic epidemiology studies in hereditary non-polyposis colorectal cancer (HNPCC) have the potential to radically improve assessment of disease risk such that more in idualised information can be provided to patients susceptible to developing disease. Studies of HNPCC initially focused on disease associations and the definition of the disease and its association with different cancers within the context of an inherited predisposition. With the identification of the genetic basis of HNPCC, new insights into the disease have been forthcoming and many advances in our understanding have been made. There have been many reports examining potential modifier genes in HNPCC, yet the results remain controversial as many findings have not been replicated and therefore no clear consensus as to the role of specific modifier genes has been reached. This review focuses on some of the factors associated with disease risk in HNPCC and where some of the difficulties lie in assessing the value of genetic epidemiology studies in this disorder.

KRAS mutation testing in colorectal cancer: The model for molecular pathology testing in the future

Publisher: Future Medicine Ltd

Date: 05-2016

DOI: 10.2217/CRC-2015-0009

Abstract: Somatic mutations in the KRAS gene often occur in colorectal cancer (CRC) and are predictive for poor response to EGFR blockade therapy. Over the past decade, routine detection of KRAS mutations has been employed in many diagnostic centers using a range of methodological approaches including Sanger sequencing, pyrosequencing, high-resolution melt analysis and more recently, next-generation sequencing approaches. This article highlights the clinical relevance of KRAS-mutated CRCs, examines advantages and disadvantages of various detection methods and highlights the considerations that are critical for an accurate, rapid and efficient workflow to detect KRAS and other RAS mutations in CRC presently and in the future.

Innate immune activation in neutrophilic asthma and bronchiectasis

Publisher: BMJ

Date: 03-2007

DOI: 10.1136/THX.2006.061358

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

Publisher: Public Library of Science (PLoS)

Date: 28-10-2016

DOI: 10.1371/JOURNAL.PGEN.1006343

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Publisher: Springer Science and Business Media LLC

Date: 27-04-2016

DOI: 10.1038/NCOMMS11375

Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations ( P × 10 −8 ) with oestrogen receptor (ER)-negative breast cancer and BRCA1 -associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5 , a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations ( P .05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population

Publisher: Public Library of Science (PLoS)

Date: 23-07-2018

DOI: 10.1371/JOURNAL.PONE.0201065

Genetic feedback to reduce alcohol consumption in hospital outpatients with risky drinking: Feasibility and acceptability

Publisher: The Sax Institute

Date: 2016

DOI: 10.17061/PHRP2641645

Abstract: There have been no trials in healthcare settings of genetic susceptibility feedback in relation to alcohol consumption. The purpose of this study was to determine the feasibility and acceptability of conducting a full-scale randomised trial estimating the effect of personalised genetic susceptibility feedback on alcohol consumption in hospital outpatients with risky drinking. Outpatients ≥18 years of age who reported drinking more than 14 standard drinks in the past week or in a typical week were asked to provide a saliva s le for genetic testing. Genetic susceptibility feedback was posted to participants 6 months after recruitment. The co-primary outcomes were the proportion of participants who (i) provided a saliva s le that could be genotyped, and (ii) spoke with a genetic counsellor. Secondary outcomes included changes in patients' weekly alcohol consumption scores on scales measuring readiness to change, importance of changing and confidence in ability to change drinking habits knowledge about which cancers are alcohol-attributable and acceptability of the saliva collection procedure and the genetic-feedback intervention. McNemar's test and paired t-tests were used to test for differences between baseline and follow-up in proportions and means, respectively. Of 100 participants who provided a saliva s le, 93 had adequate DNA for at least one genotyping assay. Three participants spoke to a genetic counsellor. Patients' readiness to change their drinking, their views on the importance of changing and their stated confidence in their ability to change increased between baseline and follow-up. There was no increase in patients' knowledge about alcohol-attributable cancers nor any reduction in how much alcohol they drank 4 months after receiving the feedback. Most participants (80%) were somewhat comfortable or very comfortable with the process used to collect saliva, 84% understood the genetic feedback, 54% found it useful, 10% had sought support to reduce their drinking after receiving the feedback, and 37% reported that the feedback would affect how much they drink in the future. Results of this study suggest it would be feasible to conduct a methodologically robust trial estimating the effect of genetic susceptibility feedback on alcohol consumption in hospital outpatients with risky drinking.

Association of Forced Vital Capacity with the Developmental Gene NCOR2

Publisher: Public Library of Science (PLoS)

Date: 02-02-2016

DOI: 10.1371/JOURNAL.PONE.0147388

Epigenetic differences at the HTR2A locus in progressive multiple sclerosis patients

Publisher: Springer Science and Business Media LLC

Date: 17-12-2020

DOI: 10.1038/S41598-020-78809-X

Abstract: The pathology of progressive multiple sclerosis (MS) is poorly understood. We have previously assessed DNA methylation in the CD4 + T cells of relapsing–remitting (RR) MS patients compared to healthy controls and identified differentially methylated regions (DMRs) in HLA-DRB1 and RNF39 . This study aimed to investigate the DNA methylation profiles of the CD4 + T cells of progressive MS patients. DNA methylation was measured in two separate case/control cohorts using the Illumina 450K/EPIC arrays and data was analysed with the Chip Analysis Methylation Pipeline (ChAMP). Single nucleotide polymorphisms (SNPs) were assessed using the Illumina Human OmniExpress24 arrays and analysed using PLINK. Expression was assessed using the Illumina HT12 array and analysed in R using a combination of Limma and Illuminaio. We identified three DMRs at HTR2A , SLC17A9 and HDAC4 that were consistent across both cohorts. The DMR at HTR2A is located within the bounds of a haplotype block however, the DMR remained significant after accounting for SNPs in the region. No expression changes were detected in any DMRs. HTR2A is differentially methylated in progressive MS independent of genotype. This differential methylation is not evident in RRMS, making it a potential biomarker of progressive disease.

Rare germline copy number deletions of likely functional importance are implicated in endometrial cancer predisposition

Publisher: Springer Science and Business Media LLC

Date: 09-11-2014

DOI: 10.1007/S00439-014-1507-4

Combined analysis of three lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers

Publisher: Wiley

Date: 11-10-2012

DOI: 10.1002/IJC.27843

Abstract: Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three s le populations combined totaling 1,352 in iduals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in in iduals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program.

Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study

Publisher: American Society of Clinical Oncology (ASCO)

Date: 11-2015

DOI: 10.1200/JCO.2014.58.9952

Abstract: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m 2 increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96 P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75 95% CI, 1.12 to 6.79 P = .03). Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.

Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma

Publisher: BMJ

Date: 23-07-2011

DOI: 10.1136/THX.2010.157719

Abstract: The well-characterised airway inflammatory phenotypes of asthma include eosinophilic, neutrophilic, mixed eosinophilic/neutrophilic and paucigranulocytic asthma, identified based on the proportion of sputum granulocytes. Systemic inflammation is now recognised as an important part of some airway diseases, but the involvement of systemic inflammation in the pathogenesis of airway inflammatory phenotypes of asthma remains unknown. Induced sputum s les and peripheral blood were collected from participants with asthma (n=36). Airway inflammatory cell counts were performed from induced sputum and inflammatory phenotype assigned based on the airway eosinophil and neutrophil cut-offs of 3% and 61%, respectively. RNA was extracted from whole blood and gene expression profiles were generated (Illumina Humanref-8 V3) and analysed using GeneSpring GX11. There were six genes classified as differentially expressed between the four asthma phenotypes, including the α-defensins (DEFA) 1, 1B, 3 and 4 and neutrophil proteases cathepsin G (CTSG) and elastase (ELA2). Systemic expression of DEFA1,1B,3,4,CTSG and ELA2 was significantly higher in the neutrophilic asthma (NA) phenotype. Microarray results of the α-defensins and neutrophil proteases were successfully validated using real-time PCR. Plasma elastase was significantly increased in people with neutrophilic airway inflammation. There is systemic upregulation of α-defensin and neutrophil protease expression in NA, which may represent proinflammatory effects on the bone marrow and the release of immature neutrophils into the circulation. This demonstrates a systemic inflammatory component in NA that further differentiates this from other asthma phenotypes and indicates different mechanisms in NA.

GISCOME – Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study

Publisher: SAGE Publications

Date: 19-04-2017

DOI: 10.1177/2396987317704547

Abstract: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60–190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.

Nucleotide excision repair gene expression after cisplatin treatment in melanoma

Publisher: American Association for Cancer Research (AACR)

Date: 13-10-2010

DOI: 10.1158/0008-5472.CAN-10-0161

Abstract: Two of the hallmark features of melanoma are its development as a result of chronic UV radiation exposure and the limited efficacy of cisplatin in the disease treatment. Both of these DNA-damaging agents result in large helix-distorting DNA damage that is recognized and repaired by nucleotide excision repair (NER). The aim of this study was to examine the expression of NER gene transcripts, p53, and p21 in melanoma cell lines treated with cisplatin compared with melanocytes. Basal expression of all genes was greater in the melanoma cell lines compared with melanocytes. Global genome repair (GGR) transcripts showed significantly decreased relative expression (RE) in melanoma cell lines 24 hours after cisplatin treatment. The basal RE of p53 was significantly higher in the melanoma cell lines compared with the melanocytes. However, induction of p53 was only significant in the melanocytes at 6 and 24 hours after cisplatin treatment. Inhibition of p53 expression significantly decreased the expression of all the GGR transcripts in melanocytes at 6 and 24 hours after cisplatin treatment. Although the RE levels were lower with p53 inhibition, the induction of the GGR genes was very similar to that in the control melanocytes and increased significantly across the time points. The findings from this study revealed reduced GGR transcript levels in melanoma cells 24 hours after cisplatin treatment. Our findings suggest a possible mechanistic explanation for the limited efficacy of cisplatin treatment and the possible role of UV light in melanoma. Cancer Res 70(20) 7918–26. ©2010 AACR.

Understanding xeroderma pigmentosum complementation groups using gene expression profiling after UV-light exposure

Publisher: MDPI AG

Date: 14-07-2015

DOI: 10.3390/IJMS160715985

Paternal impacts on development: identification of genomic regions vulnerable to oxidative DNA damage in human spermatozoa

Publisher: Oxford University Press (OUP)

Date: 10-2019

DOI: 10.1093/HUMREP/DEZ153

Abstract: Do all regions of the paternal genome within the gamete display equivalent vulnerability to oxidative DNA damage? Oxidative DNA damage is not randomly distributed in mature human spermatozoa but is instead targeted, with particular chromosomes being especially vulnerable to oxidative stress. Oxidative DNA damage is frequently encountered in the spermatozoa of male infertility patients. Such lesions can influence the incidence of de novo mutations in children, yet it remains to be established whether all regions of the sperm genome display equivalent susceptibility to attack by reactive oxygen species. Human spermatozoa obtained from normozoospermic males (n = 8) were split into equivalent s les and subjected to either hydrogen peroxide (H2O2) treatment or vehicle controls before extraction of oxidized DNA using a modified DNA immunoprecipitation (MoDIP) protocol. Specific regions of the genome susceptible to oxidative damage were identified by next-generation sequencing and validated in the spermatozoa of normozoospermic males (n = 18) and in patients undergoing infertility evaluation (n = 14). Human spermatozoa were obtained from normozoospermic males and ided into two identical s les prior to being incubated with either H2O2 (5 mm, 1 h) to elicit oxidative stress or an equal volume of vehicle (untreated controls). Alternatively, spermatozoa were obtained from fertility patients assessed as having high basal levels of oxidative stress within their spermatozoa. All semen s les were subjected to MoDIP to selectively isolate oxidized DNA, prior to sequencing of the resultant DNA fragments using a next-generation whole-genomic sequencing platform. Bioinformatic analysis was then employed to identify genomic regions vulnerable to oxidative damage, several of which were selected for real-time quantitative PCR (qPCR) validation. Approximately 9000 genomic regions, 150–1000 bp in size, were identified as highly vulnerable to oxidative damage in human spermatozoa. Specific chromosomes showed differential susceptibility to damage, with chromosome 15 being particularly sensitive to oxidative attack while the sex chromosomes were protected. Susceptible regions generally lay outside protamine- and histone-packaged domains. Furthermore, we confirmed that these susceptible genomic sites experienced a dramatic (2–15-fold) increase in their burden of oxidative DNA damage in patients undergoing infertility evaluation compared to normal healthy donors. The limited number of s les analysed in this study warrants external validation, as do the implications of our findings. Selection of male fertility patients was based on high basal levels of oxidative stress within their spermatozoa as opposed to specific sub-classes of male factor infertility. The identification of genomic regions susceptible to oxidation in the male germ line will be of value in focusing future analyses into the mutational load carried by children in response to paternal factors such as age, the treatment of male infertility using ART and paternal exposure to environmental toxicants. Project support was provided by the University of Newcastle’s (UoN) Priority Research Centre for Reproductive Science. M.J.X. was a recipient of a UoN International Postgraduate Research Scholarship. B.N. is the recipient of a National Health and Medical Research Council of Australia Senior Research Fellowship. Authors declare no conflict of interest.

LncRNA REG1CP promotes tumorigenesis through an enhancer complex to recruit FANCJ helicase for REG3A transcription

Publisher: Springer Science and Business Media LLC

Date: 25-11-2019

DOI: 10.1038/S41467-019-13313-Z

Abstract: Protein products of the regenerating islet-derived ( REG ) gene family are important regulators of many cellular processes. Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. REG1CP forms an RNA–DNA triplex with a homopurine stretch at the distal promoter of the REG3A gene, through which the DNA helicase FANCJ is tethered to the core promoter of REG3A where it unwinds double stranded DNA and facilitates a permissive state for glucocorticoid receptor α (GRα)-mediated REG3A transcription. As such, REG1CP promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. REG1CP is also transcriptionally inducible by GRα, indicative of feedforward regulation. These results reveal the function and regulation of REG1CP and suggest that REG1CP may constitute a target for cancer treatment.

Genetic and Environmental Factors Affecting TNF-α Responses in Relation to Sudden Infant Death Syndrome

Publisher: Frontiers Media SA

Date: 27-07-2015

DOI: 10.3389/FIMMU.2015.00374

Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1

Publisher: Elsevier BV

Date: 10-2015

DOI: 10.1016/J.BIOPSYCH.2015.01.003

Prevalence of clinically actionable genotypes and medication exposure of older adults in the community

Publisher: Informa UK Limited

Date: 2017

DOI: 10.2147/PGPM.S123719

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

Publisher: Springer Science and Business Media LLC

Date: 05-10-2020

DOI: 10.1038/S41467-020-18735-8

Abstract: The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14 ARF in human and p19 ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst erse cancer types and is shown to support cell survival, ision and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.

The association of the COMT V158M polymorphism with endometrial/ovarian cancer in HNPCC families adhering to the Amsterdam criteria

Publisher: Springer Science and Business Media LLC

Date: 2006

DOI: 10.1186/1897-4287-4-2-94

Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome

Publisher: Wiley

Date: 22-03-2017

DOI: 10.1111/CGE.12994

Abstract: Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases. To reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient s les for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed. We identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well-established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected. In conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach.