Dataset Information

Genome-wide association study of endometrial cancer in E2C2.

ABSTRACT: Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.

SUBMITTER: De Vivo I

PROVIDER: S-EPMC3898362 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association study of endometrial cancer in E2C2.

De Vivo Immaculata I Prescott Jennifer J Setiawan Veronica Wendy VW Olson Sara H SH Wentzensen Nicolas N Attia John J Black Amanda A Brinton Louise L Chen Chu C Chen Constance C Cook Linda S LS Crous-Bou Marta M Doherty Jennifer J Dunning Alison M AM Easton Douglas F DF Friedenreich Christine M CM Garcia-Closas Montserrat M Gaudet Mia M MM Haiman Christopher C Hankinson Susan E SE Hartge Patricia P Henderson Brian E BE Holliday Elizabeth E Horn-Ross Pamela L PL Hunter David J DJ Le Marchand Loic L Liang Xiaolin X Lissowska Jolanta J Long Jirong J Lu Lingeng L Magliocco Anthony M AM McEvoy Mark M O'Mara Tracy A TA Orlow Irene I Painter Jodie N JN Pooler Loreall L Rastogi Radhai R Rebbeck Timothy R TR Risch Harvey H Sacerdote Carlotta C Schumacher Fredrick F Scott Rodney J RJ Sheng Xin X Shu Xiao-ou XO Spurdle Amanda B AB Thompson Deborah D Vanden Berg David D Weiss Noel S NS Xia Lucy L Xiang Yong-Bing YB Yang Hannah P HP Yu Herbert H Zheng Wei W Chanock Stephen S Kraft Peter P

Human genetics 20131006 2

Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected ...[more]

PMID: 24096698

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Project description:BackgroundOestrone, predominantly made in fat, is the main circulating oestrogen and important for target tissue oestradiol production in women after menopause. The present study was undertaken to determine the genetic regulation of blood oestrone, measured with precision, in postmenopausal women and to explore associations between the identified genetic loci and endometrial cancer in a large, independent cohort.MethodsA genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components.FindingsThe median age of the 4951 women included in the GWAS was 75.9 years (range 70-94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10-8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82-0.93]; p = 6.69 × 10-5 for women across all ages and aOR 0.89 [95% CI 0.83-0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk.InterpretationWe have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue.FundingThe ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).

Dataset Information

Genome-wide association study of endometrial cancer in E2C2.

Publications

Genome-wide association study of endometrial cancer in E2C2.

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