Repository logo
 

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


Change log

Authors

O'Mara, Tracy A 
Glubb, Dylan M 
Painter, Jodie N 
Cheng, Timothy 

Abstract

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

Description

Keywords

ESR1, endometrial cancer, fine-mapping analysis, single-nucleotide polymorphisms, Breast Neoplasms, Case-Control Studies, Computational Biology, Cytoskeletal Proteins, Databases, Genetic, Endometrial Neoplasms, Estrogen Receptor alpha, Female, Genetic Loci, Genetic Predisposition to Disease, Genotype, Humans, Meta-Analysis as Topic, Nerve Tissue Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, Prognosis, Promoter Regions, Genetic, Risk Factors

Journal Title

Endocr Relat Cancer

Conference Name

Journal ISSN

1351-0088
1479-6821

Volume Title

22

Publisher

Bioscientifica
Sponsorship
National Cancer Institute (U19CA148537)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
European Commission (223175)
Cancer Research UK (16565)
Cancer Research Uk (None)
Cancer Research UK (10710)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research UK (16563)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
This work was supported by the National Health and Medical Research Council of Australia (ID#1031333 to A B Spurdle, DF, A M Dunning, ID#39435 to ANECS, ID#552402, QIMR Controls); National Health and Medical Research Council of Australia Fellowship Scheme (to A B Spurdle); Principal Research Fellow of Cancer Research UK (to D F Easton); Joseph Mitchell Trust (to A M Dunning); Oxford Comprehensive Biomedical Research Centre (to I Tomlinson); The European Community's Seventh Framework Programme (grant agreement number 22175 (HEALTH-F2-2009-223175) (COGS); Cancer Research UK (C1287/A10118 to COGS and BCAC, C1287/A10710, C12292/A11174, C1281/A12014 to COGS and BCAC, C5047/A15007, C5047/A10692, C8197/A16565, C490/A10124 to SEARCH, CORGI - NSECG, to I Tomlinson); National Institutes of Health (CA128978, R01 CA122443 to MECS and MAY, P30 CA15083 to MECS, P50 CA136393 to MECS and MAY, CAHRES); Post-Cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, 1U19 CA148112 – the GAME-ON initiative); Department of Defence (W81XWH-10-1-0341); Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; The Breast Cancer Research Foundation; Ovarian Cancer Research Fund (to COGS); Cancer Council Queensland (ID#4196615 to ANECS); Council Cancer Tasmania (ID#403031, #ID457636 to ANECS); Medical Research Council (G0000934 to the British 1958 Birth Cohort); Wellcome Trust (068545/Z/02, 085475 to the British 1958 Birth Cohort); Wellcome Trust Human Genetics Grant (090532/Z/09/Z to NSECG); European Union (EU FP7 CHIBCHA to NSECG); The University of Newcastle (to QIMR Controls, to NECS); Gladys M Brawn Senior Research Fellowship (QIMR Controls); The Vincent Fairfax Family Foundation (QIMR Controls); Hunter Medical Research Institute (HCS, NECS); Hunter Area Pathology Service (HCS); ELAN fund of the University of Erlangen (BECS); Verelst Foundation for endometrial cancer (LES); Fred C and Katherine B Anderson Foundation (to MECS, to MAY); Mayo Foundation (to MECS, to MAY); Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith (MECS, PPD/RPCI.07 to OCAC); Helse Vest Grant (MoMaTEC); University of Bergen (MoMaTEC); Melzer Foundation (MoMaTEC); The Norwegian Cancer Society – Harald Andersens legat (MoMaTEC); The Research Council of Norway (MoMaTEC); Haukeland University of Hospital (MoMaTEC); NBN Children's Cancer Research Group (NECS); Ms Jennie Thomas (NECS); regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (20110222, 20110483, 20110141 and DF 07015 all to RENDOCAS, to KARBAC); The Swedish Labor Market Insurance (100069 to RENDOCAS); The Swedish Cancer Society (11 0439 to RENDOCAS); Agency for Science, Technology and Research of Singapore (CAHRES); Susan G Komen Breast Cancer Foundation (CAHRES); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge (OCAC); Baden-Württemberg state Ministry of Science, Research and Arts (ESTHER); Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (ESTHER); Federal Ministry of Education and Research (BMBF) Germany (01KW9975/5 to GENICA, 01KW9976/8 to GENICA, 01KW9977/0 to GENICA, 01KW0114 to GENICA, to ESTHER); Robert Bosch Foundation (GENICA); Deutsches Krebsforschungszentrum – DKFZ (GENICA); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, IPA (GENICA); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus (GENICA); Deutsche Krebshilfe e.V. (70-2892-BR I to MARIE); Hamburg Cancer Society (MARIE); German Cancer Research Center (MARIE); Breast Cancer Research Foundation (MCBCS); David F. and Margaret T. Grohne Family Foundation (MCBCS); Ting Tsung and Wei Fong Chao Foundation (MCBCS); VicHealth (MCCS); Cancer Council Victoria (MCCS); Breakthrough Breast Cancer (UKBGS); Institute of Cancer Research (UKBGS); and NHS funding to the NIHR Biomedical Research Centre (UKBGS/ICR).