ORCID Profile
0000-0003-4621-1703
Current Organisations
University of Queensland School of Medicine
,
University of Tasmania
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Solid Tumours | Haematological Tumours | Oncology and Carcinogenesis | Cancer Genetics
Inherited Diseases (incl. Gene Therapy) | Cancer and Related Disorders |
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0161-6420(01)00654-6
Abstract: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). Cross-sectional genetic study. Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. From the eight pedigrees, 29 Gln368STOP mutation-carrying in iduals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 in iduals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these in iduals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more in iduals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.
Publisher: Wiley
Date: 27-08-2014
DOI: 10.1111/AJO.12241
Abstract: Vulvar cancer is a relatively rare gynaecological malignancy, the treatment of which is associated with significant patient morbidity. With reports that the incidence of vulvar cancer is increasing, there is a rising need for improved preventive, diagnostic and therapeutic tools. Recent advances within genetics and epigenetics present possible approaches for addressing this need, by contributing to the clarification of the aetiology of this disease, identifying screening and drug targets and introducing the potential for personalised treatments. This paper reviews the genetic and epigenetic research undertaken to date within vulvar cancer, evaluates its potential for clinical application and identifies directions for future research.
Publisher: Wiley
Date: 15-09-2008
DOI: 10.1002/PROS.20798
Abstract: Examination of variants of the alpha-methylacyl-CoA racemase (AMACR) gene, as genetic contributors to prostate cancer risk, has been of considerable interest given the gene's recently established role as a diagnostic biomarker for prostate cancer. The AMACR gene variants, M9V and D175G, were genotyped in a familial dataset comprising 127 cases and in a second sporadic prostate cancer dataset comprising 414 cases and 319 controls. Genotype-disease associations were examined employing the M(QLS) test and unconditional logistic regression. Differences in allele frequencies were examined using the Fisher's exact test. Association between the AMACR haplotypes and prostate cancer risk was also investigated using haplo.score. Significant evidence for association with prostate cancer risk for both the M9V and D175G variants was observed in the Tasmanian prostate cancer dataset. Whilst this association remained significant, it was diminished when relatedness amongst the familial prostate cancer cases was considered. This study, performed in a relatively genetically homogenous Tasmanian population, provides further evidence for a significant association between variants within the AMACR gene and prostate cancer risk. Risk was found to be more significantly associated with AMACR gene variants in sporadic compared to familial prostate cancer cases. These findings again highlight that genetic heterogeneity in the study population should be considered when examining genetic risk factors in prostate cancer.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2018
DOI: 10.1007/S00335-018-9783-2
Abstract: A low level of inflammation is an integral part of the balance between the immune system and the microbiota in the high antigen environment of the gastrointestinal tract and maintains homeostasis. A failure of this balance can lead to chronic intestinal inflammation and increase the chances to develop colorectal cancer significantly. The underlying mechanisms that link inflammation and carcinogenesis are not clear but the molecular platforms of the inflammasomes have been implicated. Inflammasomes are molecule complexes that are assembled in response to microbial components or cellular danger signals and facilitate the production of bioactive pro-inflammatory cytokines. One inflammasome in particular, NLRP3, has been analysed extensively in its contribution to colitis and has been shown to be associated with the development of colitis-associated colorectal cancer. This review will summarise the role of NLRP3 in intestinal inflammation, discuss some of the triggers of inflammation in the gastrointestinal tract such as diet and introduce some opportunities to use this inflammasome as therapeutic target for the treatment of colitis and colitis-associated colorectal cancer.
Publisher: Spandidos Publications
Date: 24-10-2015
DOI: 10.3892/OR.2014.3568
Publisher: Wiley
Date: 04-1992
DOI: 10.1111/J.1432-1033.1992.TB16769.X
Abstract: Plasminogen-activator inhibitor type 2 (PAI-2) is a potent and primary inhibitor of urokinase-type plasminogen activator. Its production in monocytic cells is thought to play an important role in the control of localized proteolysis at sites of invasion as occurs in the control of inflammatory processes, tumor invasion and cellular differentiation. Therefore, we have investigated the mechanisms responsible for the regulation of PAI-2 gene expression in differentiating monocytic cells using the human promyelocytic cell line, HL-60, as a model. These cells are induced to differentiate to a macrophage-like phenotype in response to phorbol ester [4-phorbol-12-myristate 13-acetate (PMA)]. The levels of PAI-2 mRNA are barely detectable in undifferentiated cells, however, activation with PMA is associated with a rapid induction of PAI-2 transcripts, reaching a maximum of 25-fold in 4 h. Nuclear run on assays demonstrate that this induction is related primarily to an enhanced rate of gene transcription. Inhibition of de novo protein synthesis by cycloheximide increases PAI-2 mRNA levels in both resting (sevenfold) and PMA-treated cells (fivefold) after 4 h, but has no detectable effect on the rate of PAI-2 gene transcription. The initial apparent half-life of the induced PAI-2 mRNA, determined by actinomycin-D-decay experiments, is very short, 32 min, suggesting rapid turnover. Furthermore, the PAI-2 mRNA transcript is stabilized in the presence of cycloheximide, with a fourfold increase in the observed half-life. The results demonstrate that PAI-2 gene expression is regulated through post-transcriptional mechanisms in undifferentiated cells, while both transcriptional and post-transcriptional events govern the level of PAI-2 transcripts in cells differentiated along the monocytic pathway. Destabilization of the PAI-2 transcript may be associated with (A + U)-rich sequences found in the 3'-untranslated region of PAI-2 mRNA. The short half life and rapid, strong induction of PAI-2 point to an important, perhaps crucial, role in the differentiation of monocyte cells.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.PATHOL.2018.05.006
Abstract: Multiple endocrine neoplasia type 1 (MEN 1) has marked severity variation between in iduals with the same mutation. To investigate any relationship between promoter methylation and clinical features, blood and tissue s les were collected from 16 members of the Tasman 1 MEN 1 kindred carrying a common splice site mutation and 7 patients with sporadic MEN 1. Methylation at 39 CpGs in the MEN1 promoter were assessed in formalin fixed, paraffin embedded parathyroid tissue. Clinical disease severity markers included age at first parathyroid operation, parathyroid hormone level and corrected serum calcium levels. Six patients with sporadic hyperparathyroidism were used for comparison. Minimal methylation was observed in all patients across CpG sites 1-23. In contrast, hypermethylation was observed at CpG sites 24-31 in MEN 1 patients, a pattern not observed in patients with non-MEN 1 parathyroid disease. Mean methylation at sites 24-31 was significantly correlated with age at first parathyroid operation (r = 0.652, p = 0.041). A permutation test, utilising the mean correlation coefficient (r = -0.401) revealed a possible association between relative PHPT severity and methylation score for each significant CpG site (p < 0.103). This novel study reveals evidence supporting a possible association between altered MEN1 promoter methylation and clinical severity of disease.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 14-11-2017
DOI: 10.1002/JCP.26197
Abstract: Integrins are transmembrane adhesion receptors that play an important role in hematopoiesis by facilitating interactions between hematopoietic cells and extracellular matrix components of the bone marrow and hematopoietic tissues. These interactions are important in regulating the function, proliferation, and differentiation of hematopoietic cells, as well as their homing and mobilization in the bone marrow. Not surprisingly altered expression and function of integrins plays a key role in the development and progression of cancer including leukemias. However, the regulation of integrin gene expression is not well characterized and the mechanisms by which integrin genes are disrupted in cancer remain unclear. Here we demonstrate for the first time that a key regulator of hematopoiesis, RUNX1, binds to and regulates the promoters of both the ITGA6 and ITGB4 genes in myeloid cells. The ITGA6 and ITGB4 integrin genes form the α6β4 integrin receptor. However, our data indicate that RUNX1 functions differently at these two promoters. RUNX1 regulates ITGA6 through a consensus RUNX1 binding motif in its promoter. In contrast, although the ITGB4 promoter is also activated by RUNX1, it does so in the absence of a recognized consensus RUNX1 binding motif. Furthermore, our data suggest that regulation of ITGB4 may involve interactions between the promoter and upstream regulatory elements.
Publisher: BMJ
Date: 09-2008
Abstract: To examine whether the inverse association between birth weight and blood pressure varies by skin pigmentation and/or related genotypes. 671 children from a predominantly caucasian birth cohort were followed-up to adolescence (mean (SD) age 14.4 (0.64)). Data on birth weight, socioeconomic status, maternal antenatal smoking, adolescent blood pressure and polymorphisms of candidate genes were obtained and analysed by multiple linear regression. An increase in birth weight of 1 kg was associated with an non-significant difference in adolescent systolic blood pressure of -0.53 mm Hg (95% CI -1.72 to 0.66) per kg after adjustment for child age and cohort entry criteria. The inverse association between birth weight and systolic blood pressure was stronger for those with darker skin (> or =2% melanin) (difference in effect, p = 0.02), those with more copies of the C allele of corticotropin-releasing hormone (CRH) +T1273C (p = 0.06), and those with more copies of the short (< or =236 bp) form of the 11beta-HSD2{CA}n(repeat) microsatellite (p = 0.03). These findings add to the evidence that cortisol-related pathways may account for at least part of the observed birth weight-blood pressure associations.
Publisher: Wiley
Date: 09-2006
DOI: 10.1111/J.1442-9071.2006.01314.X
Abstract: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP). A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing. Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation. Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome.
Publisher: Wiley
Date: 08-2010
DOI: 10.1111/J.1365-2141.2010.08267.X
Abstract: A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected in iduals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P 53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0.009).
Publisher: Rockefeller University Press
Date: 06-1998
Abstract: The serine proteinase inhibitor (serpin) plasminogen activator inhibitor type 2 (PAI-2) is well characterized as an inhibitor of extracellular urokinase-type plasminogen activator. Here we show that intracellular, but not extracellular, PAI-2 protected cells from the rapid cytopathic effects of alphavirus infection. This protection did not appear to be related to an effect on apoptosis but was associated with a PAI-2–mediated induction of constitutive low-level interferon (IFN)-α/β production and IFN-stimulated gene factor 3 (ISGF3) activation, which primed the cells for rapid induction of antiviral genes. This primed phenotype was associated with a rapid development of resistance to infection by the PAI-2 transfected cells and the establishment of a persistent productive infection. PAI-2 was also induced in macrophages in response to viral RNA suggesting that PAI-2 is a virus response gene. These observations, together with the recently demonstrated PAI-2–mediated inhibition of tumor necrosis factor-α induced apoptosis, (a) illustrate that PAI-2 has an additional and distinct function as an intracellular regulator of signal transduction pathway(s) and (b) demonstrate a novel activity for a eukaryotic serpin.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-08-2008
DOI: 10.1212/01.WNL.0000323928.57408.93
Abstract: Low past sun exposure, fair skin type, and polymorphisms of the MC1R gene have been associated with multiple sclerosis (MS) risk. We aimed to investigate the interplay between melanocortin 1 receptor gene variants, red hair/fair skin phenotype, and past environmental sun exposure in MS. Population-based case-control study in Tasmania, Australia, involving 136 cases with MS and 272 controls randomly drawn from the community and matched on sex and year of birth. Measures included past sun exposure by calendar and questionnaire, spectrophotometric skin type, and MC1R genotype, with any MC1R Arg151Cys, Arg160Trp, or Asp294His alleles present denoted as red hair color (RHC) variant. The association between RHC variant genotype and MS was more evident for women (odds ratio 2.02 [1.15-3.54]) than for men (odds ratio 0.65 [0.27-1.57]) (difference in effect, p = 0.03). The RHC variant genotype was associated with behavioral sun avoidance. In addition, increasing summer sun exposure at ages 6 through 10 years was associated with reduced MS risk among those with no RHC variant (p = 0.03), but not among those with RHC variant genotype (p = 0.15 difference in effect, p = 0.02). Similar findings were evident for other past sun exposure measures and when the s le was restricted to women only. The interplay between red hair color variant genotype, red hair/fair skin phenotype, and multiple sclerosis (MS) is complex. The modification of past sun exposure by MC1R genotype provides further support that ultraviolet radiation or derivatives such as vitamin D may be causally related to a reduced MS risk.
Publisher: Frontiers Media SA
Date: 17-08-2017
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
DOI: 10.1007/S10549-021-06496-X
Abstract: ITGA2 encodes the integrin, α2 which mediates metastatic progression, and is a predictor of poor prognosis and chemoresistance in breast cancer. Decreased ITGA2 promoter methylation is implicated as a driver of increased gene expression in aggressive prostate and pancreatic tumours, however the contribution of altered methylation to ITGA2 expression changes in breast tumours has not been examined. ITGA2 gene methylation and gene expression was examined in publicly available breast cancer datasets, and ITGA2 promoter methylation was mapped by targeted bisulphite sequencing analysis in breast tumour cell lines. The expression of a putative regulatory long noncoding RNA (lncRNA) was examined by qPCR and its' functionality was investigated using gene knockdown (antisense oligonucleotides) and over expression in breast cancer cell lines. In breast tumours and breast cancer cell lines the ITGA2 promoter is largely unmethylated, with gene expression variable in tumour subtypes, irrespective of promoter methylation. A novel lncRNA (AC025180.1 ENSG00000249899), named herein I2ALR, was identified at the ITGA2 gene locus, and was variably expressed in breast tumours and breast cancer cell subtypes. I2LAR knockdown resulted in upregulation of ITGA2 gene expression, whilst over-expression of I2ALR resulted in downregulation of ITGA2 mRNA. Further, examination of two downstream targets of ITGA2 associated with breast tumor stemness and metastasis (CCND1 and ACLY), revealed concomitant gene expression changes in response to I2ALR modulation. I2ALR represents a novel regulatory molecule targeting ITGA2 expression in breast tumours a finding of significant and topical interest to the development of therapeutics targeting this integrin.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.MOLMED.2012.08.003
Abstract: Indigenous populations, in common with all populations, stand to benefit from the potential of genetic research to lead to improvements in diagnostic and therapeutic tools for a wide range of complex diseases. However, many Indigenous communities, especially ones that are isolated, are not included in genetic research efforts. This situation is largely a consequence of the challenges of ethically conducting genetic research in Indigenous communities and compounded by Indigenous peoples' negative past experiences with genetic issues. To examine ways of addressing these challenges, we review one investigation of a cancer cluster in remote Aboriginal communities in Arnhem Land, Australia. Our experiences demonstrate that genetic research can be both ethically and successfully conducted with Indigenous communities by respecting the authority of the community, involving community members, and including regular community review throughout the research process.
Publisher: Springer Science and Business Media LLC
Date: 2015
Publisher: BMJ
Date: 09-2002
DOI: 10.1136/FN.87.2.F78
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.
Publisher: Swets & Zeitlinger Publishers
Date: 2002
Publisher: Wiley
Date: 07-01-2022
DOI: 10.1002/PROS.24300
Abstract: There is strong interest in the characterisation of gene fusions and their use to enhance clinical practices in prostate cancer (PrCa). Significantly, ~50% of prostate tumours harbour a gene fusion. Inherited factors are thought to predispose to these events but, to date, only one study has investigated gene fusions in a familial context. Here, we examined the prevalence and ersity of gene fusions in 14 tumours from a single large PrCa family, PcTas9, using the TruSight® RNA Fusion Panel and Sanger sequencing validation. These fusions were then explored in The Cancer Genome Atlas (TCGA) PrCa data set ( n = 494). Overall, 64.3% of PcTas9 tumours harboured a gene fusion, including known erythroblast transformation‐specific ( ETS ) fusions involving ERG and ETV1 , and two novel gene fusions, C19orf48:ETV4 and RYBP:FOXP1 . Although 3′ ETS genes were overexpressed in PcTas9 and TCGA tumour s les, 3′ fusion of FOXP1 did not appear to alter its expression. In addition, PcTas9 fusion carriers were more likely to have lower‐grade disease than noncarriers ( p = 0.02). Likewise, TCGA tumours with high‐grade disease were less likely to harbour fusions ( p = 0.03). Our study further implicates an inherited predisposition to PrCa gene fusion events, which are associated with less aggressive tumours. This knowledge could lead to clinical strategies to predict men at risk for fusion‐positive PrCa and, thus, identify patients who are more or less at risk of aggressive disease and/or responsive to particular therapies.
Publisher: Wiley
Date: 19-11-2016
DOI: 10.1002/JCB.25246
Abstract: Activation of cytokine signaling via the leukemia inhibitory factor receptor (LIFR) plays an integral role in hematopoiesis, osteogenesis, and placental development, along with mediating neurotrophic mechanisms. However, the regulatory control of the LIFR gene has remained largely unexplored. Here, we characterize the LIFR gene as a novel target of the RUNX1 transcription factor. The RUNX1 transcription factor is an essential regulator of hematopoiesis and is a frequent target of point mutations and chromosomal alterations in leukemia. RUNX1 regulates hematopoiesis through its control of genes important for hematopoietic cell growth, proliferation, and differentiation, including a number of cytokines and cytokine receptors. LIFR is regulated by two alternate promoters: a placental-specific and a ubiquitously active general promoter. We show that both of these promoters are regulated by RUNX1. However, in myeloid cells LIFR expression is driven solely by the general LIFR promoter with our data indicating that the placental promoter is epigenetically silenced in these cells. While RUNX1 activates the LIFR general promoter, the oncogenic RUNX1-ETO fusion protein generated by the t(8 ) translocation commonly associated with acute myeloid leukemia represses promoter activity. The data presented here establish LIFR as a transcriptional target of RUNX1 and suggest that disruption of RUNX1 activity in myeloid cells may result in altered LIFR signaling in these cells.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2017
Publisher: Elsevier BV
Date: 07-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-04-2010
Publisher: Oxford University Press (OUP)
Date: 05-1999
DOI: 10.1093/HMG/8.5.899
Abstract: A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.
Publisher: Impact Journals, LLC
Date: 14-06-2016
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: American Association for Cancer Research (AACR)
Date: 07-2015
DOI: 10.1158/1055-9965.EPI-14-0317
Abstract: Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify in iduals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 in iduals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev 24(7) 1121–9. ©2015 AACR.
Publisher: Wiley
Date: 09-2008
DOI: 10.1038/OBY.2008.302
Abstract: We aimed to (i) determine the relative importance of childhood gain in upper body adiposity for insulin resistance (IR) and triglyceridemia (TG) (ii) examine whether the associations between adiposity and metabolic indices were more evident in those with the ACE DD genotype. We examined a birth cohort study of 292 children with measures in the neonatal period (day 4) including subscapular and triceps skinfolds repeat skinfold measures at age 8, cardiorespiratory (CR) fitness, IR by the homeostasis model assessment (HOMA) equation (HOMA-IR) and serum triglyceride (TG) concentrations and measures of ACE I/D gene variants. A multiple linear regression analysis incorporating a life course approach was undertaken. Childhood gain in upper body adiposity was positively associated with HOMA-IR and TG independently of neonatal skinfolds (P < or = 0.02). The magnitude of these associations was higher among those of the ACE DD genotype. For ex le, subscapular skinfold gain was not strongly associated with HOMA-IR or TG among those with II or ID genotype (b = 0.03, P = 0.05 b = 0.02, P = 0.18 respectively) but was positively associated among those with the DD genotype (b = 0.11, P = 0.001 b = 0.08, P = 0.003) difference in effect P = 0.05 P = 0.01 respectively. Upper body fat accumulation during childhood was positively associated with HOMA-IR and TG independently of neonatal skinfolds. Further, the stronger associations for those with the ACE DD genotype is consistent with randomised controlled trial findings that ACE inhibition is associated with a reduced risk of developing type 2 diabetes. Further work is required to confirm and extend these findings.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.TRANSCI.2013.07.011
Abstract: We began epidemiological studies of haematological malignancies (lymphomas, leukaemias and related diseases) in Tasmania, the island state of Australia, in 1972. Our work has identified a number of families each containing several cases. In contrast to reports from elsewhere, we recognised familial cases incorporating the range of haematological malignancies, that is, not confined to a single diagnosis. Furthermore the average number of cases per extended family tree has exceeded that of any prior report. An unexpected discovery from the detailed familial analysis was that of anticipation, the phenomenon whereby the symptoms of a disorder become apparent at an earlier age as it is passed on to the next generation. These findings strengthen the case for there being genetic anomalies underlying the development of haematological malignancies at least in some cases, and are the subject of ongoing research.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2017
DOI: 10.1038/S41598-017-18217-W
Abstract: The HOXB13 G84E variant is associated with risk of prostate cancer (PCa), however the role this variant plays in PCa development is unknown. This study examined 751 cases, 450 relatives and 355 controls to determine the contribution of this variant to PCa risk in Tasmania and investigated HOXB13 gene and protein expression in tumours from nine G84E heterozygote variant and 13 wild-type carriers. Quantitative PCR and immunohistochemistry showed that HOXB13 gene and protein expression did not differ between tumour s les from variant and wild-type carriers. Allele-specific transcription revealed that two of seven G84E carriers transcribed both the variant and wild-type allele, while five carriers transcribed the wild-type allele. Methylation of surrounding CpG sites was lower in the variant compared to the wild-type allele, however overall methylation across the region was very low. Notably, tumour characteristics were less aggressive in the two variant carriers that transcribed the variant allele compared to the five that did not. This study has shown that HOXB13 expression does not differ between tumour tissue of G84E variant carriers and non-carriers. Intriguingly, the G84E variant allele was rarely transcribed in carriers, suggesting that HOXB13 expression may be driven by the wild-type allele in the majority of carriers.
Publisher: Cold Spring Harbor Laboratory
Date: 13-04-2022
DOI: 10.1101/2022.04.11.22273677
Abstract: Knowledge of rare, inherited variants in DNA damage repair (DDR) genes is informing clinical management in common cancers. However, defining the rare disease- associated variants in prostate cancer (PrCa) is challenging due to their low frequency. Here, whole-genome and -exome sequencing data from two independent, high- risk Australian and North American familial PrCa datasets were interrogated for novel, rare DDR variants. Segregating, high-risk, likely pathogenic DDR gene variants were identified and subsequently genotyped in 1,963 in iduals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls) and association analyses performed accounting for relatedness (M QLS ). Rare variants significantly associated with PrCa risk were identified in ERCC3 (rs145201970, p=2.57×10 −4 ) and BRIP1 (rs4988345, p=0.025) in the combined datasets. A PARP2 (rs200603922, p=0.028) variant in the Australian dataset and a MUTYH (rs36053993, p=0.031) variant in the North American dataset were also associated with PrCa risk. No evidence for a younger age or higher-grade disease at diagnosis was evident in variant carriers. Here, we provide new evidence for four novel germline DDR PrCa risk variants. Defining the full spectrum of PrCa associated DDR genes is important for effective clinical screening and disease management.
Publisher: Public Library of Science (PLoS)
Date: 07-12-2017
Publisher: Elsevier BV
Date: 06-1997
Publisher: InTech
Date: 25-11-2011
DOI: 10.5772/1285
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: Oxford University Press (OUP)
Date: 04-05-2016
DOI: 10.1093/JLB/LSW018
Publisher: Wiley
Date: 15-09-1998
DOI: 10.1046/J.1432-1327.1998.2560550.X
Abstract: The plasminogen activator inhibitor type 2 (PAI-2) gene encodes a serine proteinase inhibitor (serpin) which is rapidly induced in response to the inflammatory cytokine, tumour necrosis factor-alpha (TNFalpha) in monocytes and macrophages. As an initial step towards understanding the molecular mechanisms underlying PAI-2 gene regulation in monocytes, we report here the analysis of the chromatin structure of 9.6 kb of 5' flanking region of the human PAI-2 gene for potential cis-acting regulatory regions using DNase I hypersensitivity mapping. Sites sensitive to DNase I were mapped in two monocytic cell lines representative of early monocytic differentiation U937 cells, which synthesise low constitutive levels of PAI-2 that were induced following treatment with TNFalpha, and a MonoMac6 cell line which did not synthesise PAI-2 even after treatment with TNFalpha. Six DNase I hypersensitive sites (DHS) were identified three upstream of the transcription initiation site (DH1, DH2, DH3) and three downstream of the transcription initiation site which were contained within intron A (DH4, DH5) and the exon 2/intron B junction (DH6). Among these, one distally located DH site (DH2) disappeared in both cell lines following treatment with TNFalpha. Two DH sites (DH1, DH6) were absent in PAI-2-producing U937 cells, but were present in MonoMac6 cells, which did not produce PAI-2, indicating the possible involvement of negative regulatory elements in the suppression of PAI-2 gene expression. The results demonstrate the involvement of chromatin structure in transcriptional responsiveness of the PAI-2 gene promoter and identify several loci which may be key control regions for PAI-2 gene transcription.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0002-9394(00)00812-6
Abstract: To identify a rapid and reliable method to detect the Glutamine 368 STOP (Q368STOP) disease-predisposing allele of the myocilin gene associated with adult onset, primary, open-angle glaucoma. In iduals with the Q368STOP mutation of the myocilin gene were identified from a cohort of primary open-angle glaucoma patients from Tasmania and subjected to Taa1 restriction digestion. In the Tasmanian family presented, screening with the Taa1 restriction enzyme successfully confirmed identification of all in iduals with the Q368STOP mutation. The use of the Taa1 restriction enzyme offers a relatively simple, rapid, and reproducible technique that could be applied to detect the Q368STOP mutation of the myocilin gene.
Publisher: MDPI AG
Date: 14-04-2015
DOI: 10.3390/MD13042327
Publisher: BMJ
Date: 2004
DOI: 10.1136/BJO.88.1.79
Abstract: Mutations of seven crystallin genes have been shown to cause familial cataract. The authors aimed to identify disease causing crystallin mutations in paediatric cataract families from south eastern Australia. 38 families with autosomal dominant or recessive paediatric cataract were examined. Three large families were studied by linkage analysis. Candidate genes at regions providing significant LOD scores were sequenced. Single stranded conformational polymorphism (SSCP) analysis was used to screen five crystallin genes in the probands, followed by direct sequencing of observed electrophoretic shifts. Mutations predicted to affect the coding sequence were subsequently investigated in the entire pedigree. A LOD score of 3.72 was obtained at the gamma-crystallin locus in one pedigree. Sequencing revealed a P23T mutation of CRYGD, found to segregate with disease. A splice site mutation at the first base of intron 3 of the CRYBA1/A3 gene segregating with disease was identified by SSCP in another large family. Five polymorphisms were also detected. Although mutations in the five crystallin genes comprehensively screened in this study account for 38% of paediatric cataract mutations in the literature, only two causative mutations were detected in 38 pedigrees, suggesting that crystallin mutations are a relatively rare cause of the cataract phenotype in this population.
Publisher: BMJ
Date: 12-2021
DOI: 10.1136/BMJRESP-2021-001127
Abstract: Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening. A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two ided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two ided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two ided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population. Ethics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences. NCT04638517 Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).
Publisher: BMJ
Date: 12-2002
Abstract: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.
Publisher: Public Library of Science (PLoS)
Date: 11-2011
Publisher: Wiley
Date: 11-10-2019
DOI: 10.1111/AJO.13075
Abstract: Vulvar cancer is rare and, as a result, is understudied. Treatment is predominantly surgery, irrespective of the type of vulvar cancer, and is associated with physical, emotional and sexual complications. A cluster of human papillomavirus (HPV)-dependent vulvar cancer patients was identified in Arnhem Land Northern Territory (NT), Australia, in which young Indigenous women were diagnosed at 70 times the national incidence rate. To assess whether women from the Arnhem Land cluster differ from women with vulvar squamous cell carcinoma (VSCC) and vulvar intraepithelial neoplasia (VIN) resident elsewhere in the NT in recurrence after treatment, disease progression and mortality. A retrospective cohort study of NT-resident women diagnosed with VIN or invasive vulvar cancer (VSCC) between 1 January 1993 and 30 June 2015 was undertaken. Time to recurrence was assessed using cumulative incidence plots and Fine and Gray competing risk regression models. Mean cumulative count was used to estimate the burden of recurrent events. Indigenous women from Arnhem Land experienced more recurrences after treatment than non-Indigenous women, the cancers recurred faster, and Indigenous women have worse survival at five years. In characterising the epidemiological features of this cluster, we have identified a particularly aggressive form of vulvar cancer. This provides a unique opportunity for elucidating the aetiopathological pathways driving vulvar cancer development that may ultimately lead to preventive and therapeutic targets for this neglected malignancy. Further, these findings have important implications for clinical practice and HPV vaccination policy in the affected population.
Publisher: Springer Science and Business Media LLC
Date: 02-1998
Abstract: The serine proteinase inhibitor (serpin), plasminogen activator inhibitor type 2 (PAI-2), has been reported to inhibit tumor necrosis factor-alpha (TNF) induced apoptosis. In order to begin to understand the molecular basis for this protection, we have investigated the importance of a structural domain within the PAI-2 molecule, the C-D interhelical region, in mediating the protective effect. The C-D interhelical region is a 33 amino acid insertion which is unique among serpins and has been implicated in transglutaminase catalyzed cross-linking of PAI-2 to cell membranes. We have constructed a mutant of PAI-2 wherein 23 amino acids are deleted from the C-D interhelical region generating a structure predicted to be homologous to the closely related, but non-inhibitory serpin, chicken ovalbumin. The PAI-2Delta65/87 deletion mutant retained inhibitory activity against its known serine proteinase target, urokinase-type plasminogen activator (uPA) however expression of this mutant in HeLa cells failed to protect from TNF-induced apoptosis. Analyses of the cellular distribution of PAI-2 showed that intracellular PAI-2, and not secreted or cell-surface PAI-2, was likely responsible for the observed protection from TNF-induced apoptosis. No evidence was found for specific cross-linking of PAI-2 to the plasma membrane in either control or TNF/cycloheximide treated cells. The data demonstrate that the PAI-2 C-D interhelical domain is functionally important in PAI-2 protection from TNF induced apoptosis and suggest a novel function for the C-D interhelical domain in the protective mechanism.
Publisher: American Society of Hematology
Date: 27-01-2011
DOI: 10.1182/BLOOD-2010-07-296475
Abstract: We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.
Publisher: Wiley
Date: 07-02-2015
DOI: 10.1002/PROS.22954
Abstract: Integrin alpha2 beta1 (α2 β1 ) plays an integral role in tumour cell invasion, metastasis and angiogenesis, and altered expression of the receptor has been linked to tumour prognosis in several solid tumours. However, the relationship is complex, with both increased and decreased expression associated with different stages of tumour metastases in several tumour types. The ITGA2 gene, which codes for the α2 subunit, was examined to investigate whether a large CpG island associated with its promoter region is involved in the differential expression of ITGA2 observed in prostate cancer. Bisulphite sequencing of the ITGA2 promoter was used to assess methylation in formalin-fixed paraffin-embedded (FFPE) prostate tumour specimens and prostate cancer cell lines, PC3, 22Rv1 and LNCaP. Changes in ITGA2 mRNA expression were measured using quantitative PCR. ITGA2 functionality was interrogated using cell migration scratch assays and siRNA knockdown experiments. Bisulphite sequencing revealed strikingly decreased methylation at key CpG sites within the promoter of tumour s les, when compared with normal prostate tissue. Altered methylation of this CpG island is also associated with differences in expression in the non-invasive LNCaP, and the highly metastatic PC3 and 22Rv1 prostate cancer cell lines. Further bisulphite sequencing confirmed that selected CpGs were highly methylated in LNCaP cells, whilst only low levels of methylation were observed in PC3 and 22Rv1 cells, correlating with ITGA2 transcript levels. Examination of the increased expression of ITGA2 was shown to influence migratory potential via scratch assay in PC3, 22Rv1 and LNCaP cells, and was confirmed by siRNA knockdown experiments. Taken together, our data supports the assertion that epigenetic modification of the ITGA2 promoter is a mechanism by which ITGA2 expression is regulated.
Publisher: Wiley
Date: 23-11-2015
DOI: 10.1002/JCP.25119
Abstract: Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia.
Publisher: Hindawi Limited
Date: 24-09-2002
DOI: 10.1002/HUMU.9066
Publisher: American Society of Hematology
Date: 06-07-2017
Publisher: Springer Science and Business Media LLC
Date: 20-09-2021
DOI: 10.1007/S10453-021-09726-3
Abstract: Pollen allergies are responsible for a considerable global public health burden, and understanding exposure is critical to addressing the health impacts. Atmospheric pollen counts are routinely used as a predictor of risk however, immune responses are triggered by specific proteins known as allergens, which occur both within and on the surface of the pollen grain. The ratio between atmospheric pollen counts and allergen concentrations (‘pollen potency’) has been shown to be inconsistent, with potentially important implications for pollen monitoring practice. Despite this, there has been no previous synthesis of the literature and our understanding of the factors that influence pollen potency remains poor. We conducted a scoping review with the aim of deriving a current understanding of: (a) the factors that influence pollen potency (b) its variation through time, between taxa and by location and (c) the implications for pollen monitoring practice. Our synthesis found that pollen potency is highly variable within and between seasons, and between locations however, much of this variability remains unexplained and has not been deeply investigated. We found no predictable pollen potency patterns relating to taxon, geography or time, and inconclusive evidence regarding possible driving factors. With respect to human health, the studies in our synthesis generally reported larger associations between atmospheric allergen loads and allergy symptoms than whole pollen counts. This suggests that pollen potency influences public health risk however, the evidence base remains limited. Further research is needed to better understand both pollen potency variability and its implications for health.
Publisher: SAGE Publications
Date: 21-04-2009
Abstract: Multiple studies have provided evidence for an association between reduced sun exposure and increased risk of multiple sclerosis (MS), an association likely to be mediated, at least in part, by the vitamin D hormonal pathway. Herein, we examine whether the vitamin D receptor ( VDR), an integral component of this pathway, influences MS risk in a population-based s le where winter sun exposure in early childhood has been found to be an important determinant of MS risk. Three polymorphisms within the VDR gene were genotyped in 136 MS cases and 235 controls, and associations with MS and past sun exposure were examined by logistic regression. No significant univariate associations between the polymorphisms, rs11574010 ( Cdx-2A G), rs10735810 ( Fok1T C), or rs731236 ( Taq1C T) and MS risk were observed. However, a significant interaction was observed between winter sun exposure during childhood, genotype at rs11574010, and MS risk ( P = 0.012), with the ‘G’ allele conferring an increased risk of MS in the low sun exposure group (≤2 h/day). No significant interactions were observed for either rs10735810 or rs731236, after stratification by sun exposure. These data provide support for the involvement of the VDR gene in determining MS risk, an interaction likely to be dependent on past sun exposure.
Publisher: MDPI AG
Date: 20-11-2014
DOI: 10.3390/JPM4040459
Publisher: Wiley
Date: 06-02-2019
Abstract: Age structure is a fundamental aspect of animal population biology. Age is strongly related to in idual physiological condition, reproductive potential and mortality rate. Currently, there are no robust molecular methods for age estimation in birds. Instead, in iduals must be ringed as chicks to establish known-age populations, which is a labour-intensive and expensive process. The estimation of chronological age using DNA methylation (DNAm) is emerging as a robust approach in mammals including humans, mice and some non-model species. Here, we quantified DNAm in whole blood s les from a total of 71 known-age Short-tailed shearwaters (Ardenna tenuirostris) using digital restriction enzyme analysis of methylation (DREAM). The DREAM method measures DNAm levels at thousands of CpG dinucleotides throughout the genome. We identified seven CpG sites with DNAm levels that correlated with age. A model based on these relationships estimated age with a mean difference of 2.8 years to known age, based on validation estimates from models created by repeated s ling of training and validation data subsets. Longitudinal observation of in iduals re-s led over 1 or 2 years generally showed an increase in estimated age (6/7 cases). For the first time, we have shown that epigenetic changes with age can be detected in a wild bird. This approach should be of broad interest to researchers studying age biomarkers in non-model species and will allow identification of markers that can be assessed using targeted techniques for accurate age estimation in large population studies.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/298732
Abstract: The genetic architecture underpinning prostate cancer is complex, polygenic and despite recent significant advances many questions remain. Advances in genetic technologies have greatly improved our ability to identify genetic variants associated with complex disease including prostate cancer. Genome-wide association studies (GWASs) and microarray gene expression studies have identified genetic associations with prostate cancer susceptibility and tumour development. The integrins feature prominently in both studies examining the underlying genetic susceptibility and mechanisms driving prostate tumour development. Integrins are cell adhesion molecules involved in extracellular and intracellular signalling and are imperative for tumour development, migration, and angiogenesis. Although several integrins have been implicated in tumour development, the roles of integrin α 2 and integrin α 6 are the focus of this paper as evidence is now emerging that these integrins are implicit in prostate cancer susceptibility, cancer stem cell biology, angiogenesis, cell migration, and metastases to bone and represent potential biomarkers and therapeutic targets. There currently exists an urgent need to develop tools that differentiate indolent from aggressive prostate cancers and predict how patients will respond to treatment. This paper outlines the evidence supporting the use of α 2 and α 6 integrins in clinical applications for tailored patient treatment.
Publisher: Wiley
Date: 12-04-2021
DOI: 10.1002/IJC.33584
Abstract: Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole‐genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G A), was identified as segregating with disease in all but two in iduals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551 odds ratio [OR] = 3.55, P = 1.20 × 10 −5 ). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild‐type cases. Although no allele‐dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild‐type s les. The gene expression signature comprised known downstream targets of EZH2 and included the top‐ranked genes, DUSP1 , FOS , JUNB and EGR1 , which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.
Publisher: Research Square Platform LLC
Date: 08-11-2021
DOI: 10.21203/RS.3.RS-1026681/V1
Abstract: Purpose ITGA2 encodes the integrin, a2 which mediates metastatic progression, and is a predictor of poor prognosis and chemoresistance in breast cancer. Decreased ITGA2 promoter methylation is implicated as a driver of increased gene expression in aggressive prostate and pancreatic tumours, however the contribution of altered methylation to ITGA2 expression changes in breast tumours has not been examined. Methods ITGA2 gene methylation and gene expression was examined in publicly available breast cancer datasets, and ITGA2 promoter methylation was mapped by targeted bisulphite sequencing analysis in breast tumour cell lines. The expression of a putative regulatory long noncoding RNA (lncRNA) was examined by qPCR and its’ functionality was investigated using gene knockdown (antisense oligonucleotides) and over expression analysis in breast cancer cell lines. Results In breast tumours and breast cancer cell lines the ITGA2 promoter is largely unmethylated, with gene expression variable in tumour subtypes, irrespective of promoter methylation. A novel lncRNA (AC025180.1 ENSG00000249899), named herein I2ALR, was identified at the ITGA2 gene locus, and was variably expressed in breast tumours and breast cancer cell subtypes. I2LAR knockdown resulted in upregulation of ITGA2 gene expression, whilst over-expression of I2ALR resulted in downregulation of ITGA2 mRNA. Further, examination of two downstream targets of ITGA2 associated with breast tumor stemness and metastasis ( CCND1 and ACLY ), revealed concomitant gene expression changes in response to I2ALR modulation. Conclusion I2ALR represents a novel regulatory molecule targeting ITGA2 expression in breast tumours a finding of significant and topical interest to the development of therapeutics targeting this integrin.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2022
DOI: 10.1007/S13402-022-00752-Y
Abstract: Integrins are integral to cell signalling and management of the extracellular matrix, and exquisite regulation of their expression is essential for a variety of cell signalling pathways, whilst disordered regulation is a key driver of tumour progression and metastasis. Most recently non-coding RNAs in the form of micro-RNA (miRNA) and long non-coding RNA (lncRNA) have emerged as a key mechanism by which tissue dependent gene expression is controlled. Whilst historically these molecules have been poorly understood, advances in ‘omic’ technologies and a greater understanding of non-coding regions of the genome have revealed that non-coding RNAs make up a large proportion of the transcriptome. This review examines the regulation of integrin genes by ncRNAs, provides and overview of their mechanism of action and highlights how exploitation of these discoveries is informing the development of novel chemotherapeutic agents in the treatment of cancer. MiRNA molecules have been the most extensively characterised and negatively regulate most integrin genes, classically regulating genes through binding to recognition sequences in the mRNA 3′-untranslated regions of gene transcripts. LncRNA mechanisms of action are now being elucidated and appear to be more varied and complex, and may counter miRNA molecules, directly engage integrin mRNA transcripts, and guide or block both transcription factors and epigenetic machinery at integrin promoters or at other points in integrin regulation. Integrins as therapeutic targets are of enormous interest given their roles as oncogenes in a variety of tumours, and emerging therapeutics mimicking ncRNA mechanisms of action are already being trialled.
Publisher: Springer Science and Business Media LLC
Date: 10-07-2011
DOI: 10.1038/NG.882
Publisher: Oxford University Press (OUP)
Date: 05-2004
DOI: 10.1093/AJE/KWH120
Abstract: The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA s les were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39 odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35 odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42 odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.
Publisher: Elsevier BV
Date: 11-1995
Publisher: Wiley
Date: 02-2010
DOI: 10.1002/ANA.21849
Publisher: Elsevier BV
Date: 30-05-2008
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.YGYNO.2014.03.566
Abstract: A cluster of vulvar cancer exists in young Aboriginal women living in remote communities in Arnhem Land, Australia. A genetic case-control study was undertaken involving 30 cases of invasive vulvar cancer and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN), and 61 controls, matched for age and community of residence. It was hypothesized that this small, isolated population may exhibit increased autozygosity, implicating recessive effects as a possible mechanism for increased susceptibility to vulvar cancer. Genotyping data from saliva s les were used to identify runs of homozygosity (ROH) in order to calculate estimates of genome-wide homozygosity. No evidence of an effect of genome-wide homozygosity on vulvar cancer and VIN in East Arnhem women was found, nor was any in idual ROH found to be significantly associated with case status. This study found further evidence supporting an association between previous diagnosis of CIN and diagnosis of vulvar cancer or VIN, but found no association with any other medical history variable. These findings do not eliminate the possibility of genetic risk factors being involved in this cancer cluster, but rather suggest that alternative analytical strategies and genetic models should be explored.
Publisher: BMJ
Date: 08-2004
Publisher: Wiley
Date: 1993
Abstract: Human colonic epithelium is exposed to varying levels of sodium butyrate, which is derived from the bacterial fermentation of dietary carbohydrate. Sodium butyrate has several effects on colonic tumor cells in vitro, including arrest of cell growth and differentiation. In the present study we have found that, in addition to a reduction in cellular proliferation, sodium butyrate induces the transient expression of plasminogen activator inhibitor type-1 (PAI-1) in the LIM 2405 human colonic tumor cell. Approximately 40% of the PAI-1 secreted is biologically active as judged by the formation of higher molecular weight, SDS-resistant complexes with urokinase plasminogen activator (uPA). The enhanced PAI-1 biosynthesis was accompanied by an increase in PAI-1 mRNA levels. During the same time period, the amount of secreted uPA remained relatively constant, but the level of cell associated uPA decreased slowly and was accompanied by a decrease in uPA mRNA levels. The uPA receptor is synthesized constitutively by these cells, and was down-regulated at both the protein and mRNA levels in response to sodium butyrate. The results demonstrate that sodium butyrate can alter the balance of components of the plasminogen activator system in a manner which favours net decreased plasminogen activator activity and suggests a role for sodium butyrate in the regulation of extracellular proteolysis.
Publisher: BMJ
Date: 06-2002
DOI: 10.1136/BJO.86.6.696
Publisher: Informa UK Limited
Date: 02-09-2014
Publisher: Springer Science and Business Media LLC
Date: 14-06-2011
DOI: 10.1007/S13148-011-0041-7
Abstract: Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2016
Publisher: Springer Science and Business Media LLC
Date: 22-02-2022
DOI: 10.1038/S41598-022-06958-2
Abstract: Men living in regional and remote areas experience disparities in prostate cancer (PrCa) diagnosis, clinical characteristics and treatment modalities. We sought to determine whether such disparities exist in PrCa patients from Tasmania a regional state of Australia with the second-highest rate of diagnosis and where over a third of residents live in outer regional and remote areas. Our study included clinicopathological data from 1526 patients enrolled in the Prostate Cancer Outcomes Registry-Tasmania. Regression analyses were undertaken to determine whether demographic, clinical and treatment variables differed between inner regional and outer regional/remote patients. Men from outer regional/remote areas were significantly more likely to reside in lower socio-economic areas, be diagnosed at a later age and with more clinically aggressive features. However, in contrast to previous studies, there were no overall differences in diagnostic or treatment method, although men from outer regional/remote areas took longer to commence active treatment and travelled further to do so. This study is the first to investigate PrCa disparities in a wholly regional Australian state and highlights the need to develop systematic interventions at the patient and healthcare level to improve outcomes in outer regional and remote populations in Australia and across the globe.
Start Date: 12-2012
End Date: 12-2018
Amount: $644,028.00
Funder: Australian Research Council
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