ORCID Profile
0000-0002-3033-5851
Current Organisation
The University of Edinburgh
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Publisher: Springer Science and Business Media LLC
Date: 13-02-2023
Publisher: Springer Science and Business Media LLC
Date: 30-03-2008
DOI: 10.1038/NG.111
Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2018
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.EJON.2006.10.007
Abstract: One of the main challenges of colorectal cancer follow-up is the detection of early disease in order to influence survival and improve outcome. Yet, the benefits of follow-up are not only related to survival. It is well documented that patients can experience an array of problems following colorectal cancer surgery which impact upon quality of life, therefore symptom management plays an important part in the overall spectrum of follow-up care. In addition, there is emerging evidence to suggest that clinical nurse specialists are well placed in the multidisciplinary team to co-ordinate such follow-up programmes. This paper reports on a pilot study designed to assess the feasibility of a follow-up programme led by nurse specialists for patients with colorectal cancer. Key outcome areas were adherence to an agreed follow-protocol, quality of life, patient and clinician satisfaction and a cost-analysis of the new model. The study was conducted over one year with 60 patients. This redesign resulted in a smoother pathway of follow-up care, improved quality of life and acceptance to both patients and clinicians alike. The introduction of a nurse-led follow-up model is expected to demonstrate cost savings over a 3 year rolling follow-up programme.
Publisher: Massachusetts Medical Society
Date: 11-12-2008
Publisher: BMJ
Date: 12-12-2017
DOI: 10.1136/GUTJNL-2017-315333
Abstract: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science risk prevention early diagnosis and screening pathology curative treatment stage IV disease and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. Fifteen critical RGs are summarised below: RG1 : Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment RG2 : Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk RG3 : Pressing need for prevention trials RG4 : Lack of integration of different prevention approaches RG5 : Lack of optimal strategies for CRC screening RG6 : Lack of effective triage systems for invasive investigations RG7 : Imprecise pathological assessment of CRC RG8 : Lack of qualified personnel in genomics, data sciences and digital pathology RG9 : Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices RG10 : Need for novel technologies/interventions to improve curative outcomes RG11 : Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment RG12 : Lack of reliable biomarkers to guide stage IV treatment RG13 : Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution RG14 : Lack of coordination of CRC research/funding RG15 : Lack of effective communication between relevant stakeholders. Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.
Publisher: Frontiers Media SA
Date: 30-05-2022
Abstract: Impairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (& years) is rising, there is little data on functional outcomes in this group. The REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, & years of age at time of diagnosis and with documented follow-up including functional outcomes. A total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%) 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%). A substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters.
Publisher: Oxford University Press (OUP)
Date: 1997
DOI: 10.1093/HMG/6.1.105
Abstract: The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations in most cases. However, the penetrance of such mutations outwith classical HNPCC kindreds is unknown because families studied to date have been specifically selected for research purposes. Using a population-based strategy, we have calculated the lifetime cancer risk associated with germline DNA mismatch repair gene mutations, irrespective of their family history. We identified 67 gene carriers whose risk to age 70 for all cancers was 91% for males and 69% for females. The risk of developing colorectal cancer was significantly greater for males than for females (74% versus 30%, P= 0.006). The risk of uterine cancer (42%) exceeded that for colorectal cancer in females, emphasising the need for uterine screening. Our findings give further insight into the biological effect of defective DNA mismatch repair. We have demonstrated a systematic approach to identifying in iduals at high risk of cancer but who may not be part of classical HNPCC families. The risk estimates derived from these analyses provide a rational basis on which to guide genetic counselling and to tailor clinical surveillance.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2010
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.EJON.2013.01.010
Abstract: Survival from rectal cancer has improved substantially. Understanding the consequences of treatment is important to optimise patient support and minimise impact on daily life. We aimed to define the long-term prevalence of pelvic dysfunction following curative rectal cancer surgery (+/- radiotherapy) within the context of overall quality of life. We evaluated bowel, urinary and sexual function and quality of life using three validated questionnaires in patients treated for rectal cancer. This group was compared to patients undergoing abdominal surgery without pelvic dissection for colon cancer during the same time period. The response rate was 57% (381/667) with a median time interval of 4.4 years. A subset of rectal patients documented persistent problems with faecal leakage (16%) requiring to alter daily activities (18%) always needing to wear a protective pad (17%) rarely or never emptying their bowels fully (31%) difficulty controlling the passage of gas (32%) and requiring to modify diet (30%). Altered bowel function was found to impact on overall quality of life. Men reported increased erectile function difficulties. Pre-operative radiotherapy was associated with increased defecation problems as was low level of anastomosis (≤6 cm). In keeping with emergent evidence, this study has quantified the extent of late adverse effects with a sub-set of rectal cancer patients reporting persistent bowel function problems. The implications are now to consider current follow-up services and to 'trial' new models of comprehensive assessment and interventions in patients who are 'at risk' of experiencing late adverse effects of treatment.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
DOI: 10.1038/S41467-019-09775-W
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2022
DOI: 10.1038/S41467-022-30489-Z
Abstract: Tumour cell plasticity is a major barrier to the efficacy of targeted cancer therapies but the mechanisms that mediate it are poorly understood. Here, we identify dysregulated RNA splicing as a key driver of tumour cell dedifferentiation in colorectal cancer (CRC). We find that Apc -deficient CRC cells have dysregulated RNA splicing machinery and exhibit global rewiring of RNA splicing. We show that the splicing factor SRSF1 controls the plasticity of tumour cells by controlling Kras splicing and is required for CRC invasion in a mouse model of carcinogenesis. SRSF1 expression maintains stemness in human CRC organoids and correlates with cancer stem cell marker expression in human tumours. Crucially, partial genetic downregulation of Srsf1 does not detrimentally affect normal tissue homeostasis, demonstrating that tumour cell plasticity can be differentially targeted. Thus, our findings link dysregulation of the RNA splicing machinery and control of tumour cell plasticity.
Publisher: Springer Science and Business Media LLC
Date: 2010
Publisher: BMJ
Date: 10-2006
Publisher: Oxford University Press (OUP)
Date: 30-01-2012
Publisher: Elsevier BV
Date: 10-2017
Publisher: Oxford University Press (OUP)
Date: 28-04-2022
DOI: 10.1093/BJS/ZNAC108
Abstract: The molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status. Anonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I–III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated. A total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent P = 1.000) and tumour budding (20.3 versus 20.5 per cent P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent P & 0.001) and KRAS (40.0 versus 24.2 per cent P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent P & 0.001 relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively). Patients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers.
Publisher: Public Library of Science (PLoS)
Date: 02-06-2011
Publisher: American Medical Association (AMA)
Date: 09-2021
DOI: 10.1001/JAMASURG.2021.2380
Abstract: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.
Publisher: Proceedings of the National Academy of Sciences
Date: 26-02-2002
Abstract: Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of in iduals, so-called “multiple” adenoma patients, have a phenotype like AAPC, with 3–99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in in iduals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative in iduals with classical polyposis seems warranted.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2010
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
DOI: 10.1038/S41467-017-02662-2
Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci ( GC, NADSYN1/DHCR7, CYP2R1, CYP24A1 ). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery s le size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants ( P = 4.7×10 −9 at rs8018720 in SEC23A , and P = 1.9×10 −14 at rs10745742 in AMDHD1 ). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2016
DOI: 10.1038/NG.3562
Publisher: Springer Science and Business Media LLC
Date: 20-04-2021
DOI: 10.1038/S41467-021-22531-3
Abstract: Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.
Publisher: Oxford University Press (OUP)
Date: 03-2012
Publisher: Wiley
Date: 12-10-2017
DOI: 10.1002/IJC.31076
Publisher: BMJ
Date: 20-03-2017
DOI: 10.1136/BMJ.J1388
Publisher: Public Library of Science (PLoS)
Date: 06-09-2013
Publisher: Public Library of Science (PLoS)
Date: 19-07-2012
Publisher: Springer Science and Business Media LLC
Date: 25-11-2016
DOI: 10.1038/NCOMMS13507
Abstract: Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP ( RPS6KA2 ) and DMRs ( VMP1, ITGB2 and TXK ) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8 + T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
Publisher: Oxford University Press (OUP)
Date: 22-03-2016
DOI: 10.1093/HMG/DDW087
Publisher: BMJ
Date: 09-12-2019
DOI: 10.1136/GUTJNL-2019-319313
Abstract: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as ‘positive’ and ‘less-credible positive’ were further validated in three large GWAS consortia conducted in populations of European origin. We initially identified 18 independent variants at 16 loci that were classified as ‘positive’ polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as ‘less-credible positive’ SNPs 72.2% of the ‘positive’ SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to ‘less-credible’ positive (reducing the ‘positive’ variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk. The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 23-09-2010
DOI: 10.1111/J.1469-1809.2010.00603.X
Abstract: Germline defects in the MLH1 gene are associated with Lynch syndrome. A substantial proportion of these mutations leads to premature termination codons and can induce nonsense mediated decay (NMD) of the corresponding transcript. Resulting allelic expression differences represent a fast and inexpensive method to identify patients carrying MLH1 mutations. In patients and controls, we show that allelic expression imbalance (AEI) can be readily detected in RNA extracted from whole blood from patients carrying mutations expected to elicit NMD using mass spectrometry. Mutations closer to the 5' end of the gene tend to show smaller imbalances. AEI can also be detected in normal controls. Analysis of allelic expression in controls and in iduals with mutations not expected to exhibit NMD revealed that MLH1 expression is influenced by sequence variation acting in cis. A maximum likelihood framework was used to identify two SNPs, rs1799977 (c.655G>A p.I219V) and rs1800734 (c.-93 G>A) that are independently associated with expression. These influences are, however, small compared to the differences associated with pathological variants.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2016
DOI: 10.1038/BJC.2016.188
Publisher: Springer Science and Business Media LLC
Date: 17-11-2009
Publisher: Springer Science and Business Media LLC
Date: 09-08-2012
DOI: 10.1038/BJC.2012.329
Publisher: Springer Science and Business Media LLC
Date: 20-12-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2015
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.
Publisher: Wiley
Date: 06-04-2017
DOI: 10.1002/IJC.30709
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Elsevier BV
Date: 12-2012
Publisher: Oxford University Press (OUP)
Date: 03-02-2010
DOI: 10.1093/JNCI/DJP473
Publisher: Oxford University Press (OUP)
Date: 10-06-2020
Abstract: Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of s les so far (4802 in iduals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo.
Publisher: Cambridge University Press (CUP)
Date: 06-03-2015
DOI: 10.1017/THG.2015.10
Abstract: Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to in idual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish in iduals were selected for high scores on a general component of intelligence ( g ). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g . Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g . The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g . Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger s les would be worthwhile.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2011
DOI: 10.1158/1940-6207.CAPR-11-0106
Abstract: Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo RS plus aspirin placebo aspirin plus RS RS placebo plus aspirin placebo they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54–1.10 versus nonaspirin arms) RS relative risk = 1.05 (95% CI, 0.73–1.49 versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin—mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02) there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas. Cancer Prev Res 4(5) 655–65. ©2011 AACR.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2007
DOI: 10.1038/NG2089
Abstract: Using a multistage genetic association approach comprising 7,480 affected in iduals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected in iduals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected in iduals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend P = 1.41 x 10(-8)) and 1.14 (trend P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected in iduals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend 95% confidence interval (c.i.): 1.07-1.26 P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23 P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.
Publisher: Public Library of Science (PLoS)
Date: 19-08-2011
Publisher: American Association for Cancer Research (AACR)
Date: 06-2006
DOI: 10.1158/1078-0432.CCR-05-2452
Abstract: Purpose: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). Experimental Design: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. Results: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P & 0.001). Conclusions: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P & 0.001).
Publisher: American Association for Cancer Research (AACR)
Date: 12-2013
DOI: 10.1158/1078-0432.CCR-13-0550
Abstract: Purpose: Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas. Experimental Design: Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10−7. Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58]. Results: Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P & 10−7 level with OR & 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241 r2 = 0.8–1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11 OR, 2.09 95% confidence interval (CI), 1.50–2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia N = 9,211). Conclusions: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance. Clin Cancer Res 19(23) 6430–7. ©2013 AACR.
Publisher: Elsevier BV
Date: 12-2011
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Publisher: Oxford University Press (OUP)
Date: 10-11-2011
DOI: 10.1093/HMG/DDR523
Publisher: Elsevier BV
Date: 04-2015
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Malcolm Dunlop.