Publications by authors named "Aung K Win"

32 Publications

Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer.

JNCI Cancer Spectr 2021 Apr 8;5(2):pkab022. Epub 2021 Mar 8.

Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Victoria, Australia.

It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes-people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 , 314 , 126 , 71 , and 22 ) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided >.05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided =.51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.
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http://dx.doi.org/10.1093/jncics/pkab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062848PMC
April 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Eur J Cancer 2021 05 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome.

Am J Epidemiol 2021 02;190(2):230-238

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.
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http://dx.doi.org/10.1093/aje/kwaa175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210745PMC
February 2021

Germline and Tumor Sequencing as a Diagnostic Tool To Resolve Suspected Lynch Syndrome.

J Mol Diagn 2021 03 29;23(3):358-371. Epub 2020 Dec 29.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Centre for Cancer Research, Victorian Comprehensive Cancer Centre, The University of Melbourne, Parkville, Victoria, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia. Electronic address:

Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene mutations using targeted, whole-exome sequencing or WGS. Germline WGS identified pathogenic MMR variants in 3 of the 14 cases (21.4%), including a 9.5-megabase inversion disrupting MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8 of 11 tumors tested (72.7%). In a second mother-daughter pair, a somatic cause of tumor MMR deficiency was supported by the presence of double somatic MSH2 mutations in their respective tumors. More than 70% of SLS cases had double somatic MMR mutations in the absence of germline pathogenic variants in the MMR or other DNA repair-related genes on WGS, and, therefore, were confidently assigned a noninherited cause of tumor MMR deficiency.
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http://dx.doi.org/10.1016/j.jmoldx.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927277PMC
March 2021

Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis.

Cancer Epidemiol Biomarkers Prev 2020 12 2;29(12):2719-2728. Epub 2020 Oct 2.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.

Background: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4 T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis.

Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC).

Results: A significant association of the SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; value: 0.03). Suggestive evidence for association was found with two SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed.

Conclusions: Common genetic variation in the Treg pathway implicating genes such as and was shown to be associated with prognosis of colorectal cancer patients.

Impact: The implicated genes warrant further investigation.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976673PMC
December 2020

Exposure to household air pollution over 10 years is related to asthma and lung function decline.

Eur Respir J 2021 01 14;57(1). Epub 2021 Jan 14.

Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia.

Introduction: We investigated if long-term household air pollution (HAP) is associated with asthma and lung function decline in middle-aged adults, and whether these associations were modified by glutathione -transferase (GST) gene variants, ventilation and atopy.

Materials And Methods: Prospective data on HAP (heating, cooking, mould and smoking) and asthma were collected in the Tasmanian Longitudinal Health Study (TAHS) at mean ages 43 and 53 years (n=3314). Subsamples had data on lung function (n=897) and GST gene polymorphisms (n=928). Latent class analysis was used to characterise longitudinal patterns of exposure. Regression models assessed associations and interactions.

Results: We identified seven longitudinal HAP profiles. Of these, three were associated with persistent asthma, greater lung function decline and % reversibility by age 53 years compared with the "Least exposed" reference profile for those who used reverse-cycle air conditioning, electric cooking and no smoking. The "All gas" (OR 2.64, 95% CI 1.22-5.70), "Wood heating/smoking" (OR 2.71, 95% CI 1.21-6.05) and "Wood heating/gas cooking" (OR 2.60, 95% CI 1.11-6.11) profiles were associated with persistent asthma, as well as greater lung function decline and % reversibility. Participants with the Ile/Ile genotype were at a higher risk of asthma or greater lung function decline when exposed compared with other genotypes. Exhaust fan use and opening windows frequently may reduce the adverse effects of HAP produced by combustion heating and cooking on current asthma, presumably through increasing ventilation.

Conclusions: Exposures to wood heating, gas cooking and heating, and tobacco smoke over 10 years increased the risks of persistent asthma, lung function decline and % reversibility, with evidence of interaction by GST genes and ventilation.
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http://dx.doi.org/10.1183/13993003.00602-2020DOI Listing
January 2021

Genetic Predictors of Circulating 25-Hydroxyvitamin D and Prognosis after Colorectal Cancer.

Cancer Epidemiol Biomarkers Prev 2020 06 18;29(6):1128-1134. Epub 2020 Mar 18.

Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival.

Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer.

Results: The 25(OH)D decreasing allele of SNP rs2282679 ( gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, = 0.02).

Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue.

Impact: Further studies are warranted to investigate the association in specific subgroups.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269850PMC
June 2020

A New Comprehensive Colorectal Cancer Risk Prediction Model Incorporating Family History, Personal Characteristics, and Environmental Factors.

Cancer Epidemiol Biomarkers Prev 2020 03 13;29(3):549-557. Epub 2020 Jan 13.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Purpose: Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention.

Methods: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases ( = 4,445) and controls ( = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based ( = 12,052) and clinic-based ( = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)].

Results: The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74-1.45) for men and 0.86 (0.64-1.20) for women, and for clinic-based relatives were 1.15 (0.87-1.58) for men and 1.04 (0.76-1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60-0.78) for men and 0.70 (0.62-0.77) for women, and for clinic-based relatives were 0.77 (0.69-0.84) for men and 0.68 (0.60-0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) for men and 0.10 (0.04-0.16) for women, and for clinic-based relatives were 0.11 (0.05-0.17) for men and 0.11 (0.06-0.17) for women.

Conclusions: Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model.

Impact: Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060114PMC
March 2020

Ability of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history.

Fam Cancer 2019 10;18(4):389-397

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia.

Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54-4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.
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http://dx.doi.org/10.1007/s10689-019-00136-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785388PMC
October 2019

Early-life exposure to sibling modifies the relationship between CD14 polymorphisms and allergic sensitization.

Clin Exp Allergy 2019 03 13;49(3):331-340. Epub 2018 Nov 13.

Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia.

Background: Markers of microbial exposure are thought to be associated with risk of allergic sensitization; however, the associations are inconsistent and may be related to gene-environment interactions.

Objective: To examine the relationship between polymorphisms in the CD14 gene and allergic sensitization and whether sibling exposure, as a marker of microbial exposure, modified this relationship.

Methods: We used data from the Tasmanian Longitudinal Health Study and the Melbourne Atopy Cohort Study. Two CD14 polymorphisms were genotyped. Allergic sensitization was defined by a positive response to a skin prick test. Sibling exposure was measured as cumulative exposure to siblings before age 6 months, 2 and 4 years. Logistic regression and multi-level mixed-effects logistic regression were used to examine the associations. Effect estimates across the cohorts were pooled using random-effects meta-analysis.

Results: CD14 SNPs were not individually associated with allergic sensitization in either cohort. In TAHS, cumulative sibling exposure before age 6 months, 2 and 4 years was each associated with a reduced risk of allergic sensitization at age 45 years. A similar effect was observed in MACS. Meta-analysis across the two cohorts showed consistent evidence of an interaction between cumulative sibling exposure before 6 months and the rs5744455-SNP (P = 0.001) but not with the rs2569190-SNP (P = 0.60). The pooled meta-analysis showed that the odds of sensitization with increasing cumulative exposure to sibling before 6 months of age was 20.9% smaller in those with the rs5744455-C-allele than the T-allele (OR = 0.83 vs 1.05, respectively).

Conclusion And Clinical Relevance: Cumulative sibling exposure reduced the risk of sensitization from childhood to middle age in genetically susceptible individuals.
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http://dx.doi.org/10.1111/cea.13290DOI Listing
March 2019

Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer.

Br J Cancer 2018 06 24;118(12):1639-1647. Epub 2018 May 24.

Department of Family Medicine and Community Health, Case Western Reserve University, Cleveland, OH, 44106, USA.

Background: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent.

Methods: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index.

Results: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results.

Conclusions: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.
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http://dx.doi.org/10.1038/s41416-018-0108-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008474PMC
June 2018

Reproductive factors as risk modifiers of breast cancer in mutation carriers and high-risk non-carriers.

Oncotarget 2017 Nov 31;8(60):102110-102118. Epub 2017 Oct 31.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

This study was conducted to identify the role of reproductive factors as environmental modifiers for breast cancer (BC) risk in clinic-based, East-Asian and mutation carriers and non-carriers with high-risk criteria of mutations (family history (FH) of BC, early-onset BC (aged ≤40 years)). A total of 581 women who were carriers (222 and 359 ), 1,083 non-carriers with FH, and 886 non-carriers with early-onset BC were enrolled and interviewed to examine the reproductive factors, from 2007 to 2014. The hazard ratio (HR) and its 95% confidence interval (CI) in the weighted Cox regression model were used to calculate the BC risk based on the reproductive factors. Earlier menarche increased BC risk by 3.49-fold in mutation carriers (95%CI=2.03-6.00) and 3.30-fold in non-carriers with FH (95%CI=1.73-6.34), but was insignificantly associated with carriers and non-carriers for early-onset BC (P-heterogeneity=0.047). Higher parity decreased BC risk in carriers and non-carriers with FH, especially in carriers (HR=0.27, 95% CI=0.09-0.83 for two parity; and HR=0.23, 95%CI=0.05-1.00 for ≥3 parity), but increased the early-onset BC risk (HR=4.63, 95%CI=2.56-8.51 for >3 parity, p-heterogeneity=0.045). Oral contraceptive (OC) use and longer estrogen exposure periods (≥30 years) were associated with an increased risk of early-onset BC (HR=3.99, 95%CI=1.65-9.67; HR=7.69, 95%CI=1.96-25.01), while OC use was not associated with BC risk in other groups and longer estrogen exposure had rather decreased risk for BC risk (both p-heterogeneity<0.001). Several reproductive factors as risk modifiers could heterogeneously be associated with BC among mutation carriers, non-carriers with FH, and early-onset BC non-carriers.
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http://dx.doi.org/10.18632/oncotarget.22193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731939PMC
November 2017

Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci.

Int J Cancer 2018 02 12;142(3):540-546. Epub 2017 Oct 12.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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http://dx.doi.org/10.1002/ijc.31076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383773PMC
February 2018

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

Mol Genet Genomic Med 2017 Sep 23;5(5):553-569. Epub 2017 Jul 23.

Department of Laboratory Medicine and PathologyMayo ClinicRochesterMinnesota.

Background: Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility.

Methods: Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X ( = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing ( = 548); (3) young onset (age <50 years) ( = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years ( = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 ( = 129). Ninety-three unaffected controls were also sequenced.

Results: Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in ,,,, or multiple pathogenic mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations.

Conclusions: Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.
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http://dx.doi.org/10.1002/mgg3.317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606870PMC
September 2017

Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis.

Eur J Cancer 2017 10 19;84:228-238. Epub 2017 Aug 19.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, 12713, Saudi Arabia.

Background: While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk.

Methods: We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels.

Results: Risk reduction was observed for oleic and palmitoleic MUFAs (OR = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10; OR = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (OR = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10; OR = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10). The SFA stearic acid was associated with increased CRC risk (OR = 1.17, 95% CI: 1.01-1.35, P = 0.041).

Conclusion: Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.
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http://dx.doi.org/10.1016/j.ejca.2017.07.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630201PMC
October 2017

Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas.

Fam Cancer 2018 01;17(1):91-100

Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.

In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility.
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http://dx.doi.org/10.1007/s10689-017-0013-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129400PMC
January 2018

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer.

Int J Cancer 2017 06 6;140(12):2701-2708. Epub 2017 Apr 6.

Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.
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http://dx.doi.org/10.1002/ijc.30709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135234PMC
June 2017

The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma.

Sci Rep 2017 03 6;7:43681. Epub 2017 Mar 6.

Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, the University of Melbourne, Victoria, Australia.

Asthma phenotypes based on age-of-onset may be differently influenced by the interaction between variation in toll-like receptor (TLR)/CD14 genes and environmental microbes. We examined the associations between single-nucleotide polymorphisms (SNP) in the TLR/CD14 genes and asthma, and their interaction with proxies of microbial exposure (childhood farm exposure and childhood rural environment). Ten SNPs in four genes (TLR2, TLR4, TLR6, CD14) were genotyped for 1,116 participants from the Tasmanian Longitudinal Health Study (TAHS). Using prospectively collected information, asthma was classified as never, early- (before 13 years) or late-onset (after 13 years). Information on childhood farm exposure/childhood rural environment was collected at baseline. Those with early-onset asthma were more likely to be males, had a family history of allergy and a personal history of childhood atopy. We found significant interaction between TLR6 SNPs and childhood farm exposure. For those with childhood farm exposure, carriers of the TLR6-rs1039559 T-allele (p-interaction = 0.009) and TLR6-rs5743810 C-allele (p-interaction = 0.02) were associated with lower risk of early-onset asthma. We suggest the findings to be interpreted as hypothesis-generating as the interaction effect did not withstand correction for multiple testing. In this large, population-based longitudinal study, we found that the risk of early- and late-onset asthma is differently influenced by the interaction between childhood farming exposure and genetic variations.
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http://dx.doi.org/10.1038/srep43681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337969PMC
March 2017

Modeling of successive cancer risks in Lynch syndrome families in the presence of competing risks using copulas.

Biometrics 2017 03 5;73(1):271-282. Epub 2016 Jul 5.

Department of Mathematics and Statistics, Laval University, Quebec, Canada.

In this article, we propose an association model to estimate the penetrance (risk) of successive cancers in the presence of competing risks. The association between the successive events is modeled via a copula and a proportional hazards model is specified for each competing event. This work is motivated by the analysis of successive cancers for people with Lynch Syndrome in the presence of competing risks. The proposed inference procedure is adapted to handle missing genetic covariates and selection bias, induced by the data collection protocol of the data at hand. The performance of the proposed estimation procedure is evaluated by simulations and its use is illustrated with data from the Colon Cancer Family Registry (Colon CFR).
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http://dx.doi.org/10.1111/biom.12561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319907PMC
March 2017

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

Br J Cancer 2016 Jul 23;115(2):266-72. Epub 2016 Jun 23.

Wellcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK.

Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.

Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls.

Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively.

Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.
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http://dx.doi.org/10.1038/bjc.2016.188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947703PMC
July 2016

The Experience of Extended Bowel Resection in Individuals With a High Metachronous Colorectal Cancer Risk: A Qualitative Study.

Oncol Nurs Forum 2016 07;43(4):444-52

University of Melbourne.

Purpose/objectives: To ascertain individual experiences of extended bowel resection as treatment for colorectal cancer (CRC) in those with a high metachronous CRC risk, including the self-reported adequacy of information received at different time points of treatment and recovery.
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Research Approach: Qualitative.
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Setting: Participants were recruited through the Australasian Colorectal Cancer Family Registry and two hospitals in Melbourne, Australia.
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Participants: 18 individuals with a high metachronous CRC risk who had an extended bowel resection from 6-12 months ago.
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Methodologic Approach: Semistructured interviews. Data were analyzed thematically.
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Findings: In most cases, the treating surgeon decided on the best option regarding surgical treatment. Participants felt well informed about the surgical procedure. Information related to surgical outcomes, recovery, and lifestyle adjustment from surgery was not always adequate. Many participants described ongoing worry about developing another cancer. 
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Conclusions: Patients undergoing an extended resection to reduce metachronous CRC risk require detailed information delivered at more than one time point and relating to several different aspects of the surgical procedure and its outcomes.
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Interpretation: An increased emphasis should be given to the provision of patient information on surgical outcomes, recovery, and lifestyle adjustment. Colorectal nurses could provide support for some of the reported unmet needs.
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http://dx.doi.org/10.1188/16.ONF.444-452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114664PMC
July 2016

Quantifying the utility of single nucleotide polymorphisms to guide colorectal cancer screening.

Future Oncol 2016 Feb 1;12(4):503-13. Epub 2016 Feb 1.

Centre for Epidemiology & Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Parkville Victoria, VIC 3010, Australia.

Aim: To determine whether single nucleotide polymorphisms (SNPs) can be used to identify people who should be screened for colorectal cancer.

Methods: We simulated one million people with and without colorectal cancer based on published SNP allele frequencies and strengths of colorectal cancer association. We estimated 5-year risks of colorectal cancer by number of risk alleles.

Results: We identified 45 SNPs with an average 1.14-fold increase colorectal cancer risk per allele (range: 1.05-1.53). The colorectal cancer risk for people in the highest quintile of risk alleles was 1.81-times that for the average person.

Conclusion: We have quantified the extent to which known susceptibility SNPs can stratify the population into clinically useful colorectal cancer risk categories.
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http://dx.doi.org/10.2217/fon.15.303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976832PMC
February 2016

Risk Prediction Models for Colorectal Cancer: A Systematic Review.

Cancer Prev Res (Phila) 2016 Jan 13;9(1):13-26. Epub 2015 Oct 13.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

Colorectal cancer is the second leading cause of cancer-related death in Europe and the United States. Survival is strongly related to stage at diagnosis and population-based screening reduces colorectal cancer incidence and mortality. Stratifying the population by risk offers the potential to improve the efficiency of screening. In this systematic review we searched Medline, EMBASE, and the Cochrane Library for primary research studies reporting or validating models to predict future risk of primary colorectal cancer for asymptomatic individuals. A total of 12,808 papers were identified from the literature search and nine through citation searching. Fifty-two risk models were included. Where reported (n = 37), half the models had acceptable-to-good discrimination (the area under the receiver operating characteristic curve, AUROC >0.7) in the derivation sample. Calibration was less commonly assessed (n = 21), but overall acceptable. In external validation studies, 10 models showed acceptable discrimination (AUROC 0.71-0.78). These include two with only three variables (age, gender, and BMI; age, gender, and family history of colorectal cancer). A small number of prediction models developed from case-control studies of genetic biomarkers also show some promise but require further external validation using population-based samples. Further research should focus on the feasibility and impact of incorporating such models into stratified screening programmes.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610622PMC
January 2016

Breast cancer risk for Korean women with germline mutations in BRCA1 and BRCA2.

Breast Cancer Res Treat 2015 Aug 21;152(3):659-65. Epub 2015 Jul 21.

Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Gyeonggi-do, Korea,

The average age-specific cumulative risk (penetrance) of breast cancer has been studied for BRCA1 and BRCA2 mutation carriers living in Western countries, but not for those living in East Asian countries where the population breast cancer incidence is lower. From 2007 to 2011, the Korean Hereditary Breast Cancer study identified 151 BRCA1 and 225 BRCA2 mutation-carrying families from family cancer clinics. We estimated the hazard ratio (HR) for female carriers relative to the population, and hence the penetrance, using a modified segregation analysis of cancer family histories conditioned on ascertainment. The breast cancer HR estimates [95 % confidence interval (CI)] for BRCA1 and BRCA2 mutation carriers were 18 (3-103) and 11 (5-27), respectively. The breast cancer penetrance estimates (95 % CI) to age 70 years were 49 % (11-98) and 35 % (16-65) for BRCA1 and BRCA2 mutation carriers, respectively. The breast cancer HR and penetrance estimates were similar for Korean and Western women (all P > 0.4). The point estimates of breast cancer penetrance were similar to age 50 years, though less for Korean carriers at older ages. Breast cancer risk for Korean and Western mutation carriers might reflect underlying population risks which in turn likely reflect differences in environmental and lifestyle factors. This raises the possibility of identifying modifiers of cancer risk for carriers with implications for prevention.
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http://dx.doi.org/10.1007/s10549-015-3495-zDOI Listing
August 2015

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Hum Pathol 2014 Oct 17;45(10):2077-84. Epub 2014 Jul 17.

Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton 3010, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC 3010, Australia.

Adenocarcinomas of the colon and rectum are graded using a 2-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas. We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with low-grade tumors (20% versus 6%; P < .001). Using Cox regression models, adjusting for sex and age at diagnosis and stratifying by the American Joint Committee on Cancer stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of all-cause and colorectal cancer-specific mortality: hazard ratio 2.09 (95% confidence interval [CI], 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P < .001. A new grading system separating adenocarcinoma into low grade (all histologic low grade and MSI high grade) and high grade (MSS histologic high grade) gave a lower Akaike information criterion value when compared with the current grading system and thus represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor.
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http://dx.doi.org/10.1016/j.humpath.2014.06.020DOI Listing
October 2014

Re: Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication.

J Natl Cancer Inst 2014 Aug 11;106(8). Epub 2014 Aug 11.

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Australia (CR, MC, RJW, MDW, DDB); Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Australia (MC, DDB); University of Queensland, School of Medicine, Herston, Australia (CR); Envoi Pathology, Herston, Australia (CR); Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia (EJW, AKW, MAJ, JLH, GGG, DRE, DDB); Department of Histopathology, Sullivan Nicolaides Pathology, Taringa, Australia (MDW); Seoul National University, Seoul, Korea (JLH); Department of Medicine, The University of Melbourne, Parkville, Australia (IW); Genetic Medicine, The Royal Melbourne Hospital, Parkville, Australia (IW); Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton, Australia (MCS); Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, Australia (GGG, DRE).

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http://dx.doi.org/10.1093/jnci/dju180DOI Listing
August 2014

Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: colon cancer family registry.

Genes Chromosomes Cancer 2014 Jul 28;53(7):568-78. Epub 2014 Mar 28.

Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120, Heidelberg, Germany.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID-metabolizing enzymes central to NSAID metabolism including UDP-glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three-SNP genotype in UGT1A6 (G-A-A; Ala7-Thr181-Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04-14.45 and OR 1.34; 95% CI 1.10-1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P-interaction = 0.02), a three-SNP genotype within UGT2B4 and ibuprofen use (P-interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P-interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326223PMC
July 2014

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.

Mod Pathol 2013 Dec 28;26(12):1642-56. Epub 2013 Jun 28.

1] Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, QLD, Australia [2] Department of Histopathology, Sullivan Nicolaides Pathology, Taringa, QLD, Australia.

Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.
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http://dx.doi.org/10.1038/modpathol.2013.101DOI Listing
December 2013

Family history of colorectal cancer in BRAF p.V600E-mutated colorectal cancer cases.

Cancer Epidemiol Biomarkers Prev 2013 May 5;22(5):917-26. Epub 2013 Mar 5.

Cancer and Population Studies Group, Queensland Institute of Medical Research, 300 Herston Rd, Herston QLD 4006, Australia.

Background: Previous reports suggest that relatives of colorectal cancer (CRC)-affected probands carrying the BRAF p.V600E mutation are at an increased risk of CRC and extracolonic cancers (ECC). In this study, we estimated the association between a family history of either CRC or ECC and risk of CRC with a BRAF p.V600E mutation.

Methods: Population-based CRC cases (probands, ages 18-59 years at diagnosis), recruited irrespective of family cancer history, were characterized for BRAF p.V600E mutation and mismatch repair (MMR) status. ORs and 95% confidence intervals (CI) were estimated using multivariable logistic regression.

Results: The 690 eligible probands showed a mean age at CRC diagnosis of 46.9 ± 7.8 years, with 313 (47.9%) reporting a family history of CRC and 53 (7.7%) that were BRAF-mutated. Probands with BRAF-mutated, MMR-proficient CRCs were less likely to have a family history of CRC than probands that were BRAF wild-type (OR, 0.46; 95% CI, 0.24-0.91; P = 0.03). For probands with a BRAF-mutated CRC, the mean age at diagnosis was greater for those with a CRC-affected first- or second-degree relative (49.3 ± 6.4 years) compared with those without a family history (43.8 ± 10.2 years; P = 0.04). The older the age at diagnosis of CRC with the BRAF p.V600E mutation, the more likely these probands were to show a family history of CRC (OR, 1.09 per year of age; 95% CI, 1.00-1.18; P = 0.04).

Conclusions: Probands with early-onset, BRAF-mutated, and MMR-proficient CRC were less likely to have a family history of CRC than probands that were BRAF-wild-type.

Impact: These findings provide useful insights for cancer risk assessment in families and suggest that familial or inherited factors are more important in early-onset, BRAF-wild-type CRC.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-1211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024397PMC
May 2013

Cancer risks for MLH1 and MSH2 mutation carriers.

Hum Mutat 2013 Mar;34(3):490-7

Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Parkville, Victoria, Australia.

We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.
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http://dx.doi.org/10.1002/humu.22262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887142PMC
March 2013
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