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

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.

• Authors: Tracy A O'Mara, Dylan M Glubb, Jodie N Painter, Timothy Cheng, Joe Dennis, Australian National Endometrial Cancer Study Group (ANECS), John Attia, Elizabeth G Holliday, Mark McEvoy, Rodney J Scott, Katie Ashton, Tony Proietto, Geoffrey Otton, Mitul Shah, Shahana Ahmed, Catherine S Healey, Maggie Gorman, Lynn Martin, National Study of Endometrial Cancer Genetics Group (NSECG), Shirley Hodgson, Peter A Fasching, Alexander Hein, Matthias W Beckmann, Arif B Ekici, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Matthias Dürst, Ingo Runnebaum, Peter Hillemanns, Thilo Dörk, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Hui Zhao, Ellen L Goode, Sean C Dowdy, Brooke L Fridley, Stacey J Winham, Helga B Salvesen, Tormund S Njølstad, Jone Trovik, Henrica M J Werner, Emma Tham, Tao Liu, Miriam Mints, RENDOCAS, Manjeet K Bolla, Kyriaki Michailidou, Jonathan P Tyrer, Qin Wang, John L Hopper, AOCS Group, Julian Peto, Anthony J Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang-Claude, Fergus J Couch, Graham G Giles, Vessela N Kristensen, Angela Cox, Paul D P Pharoah, Alison M Dunning, Ian Tomlinson, Douglas F Easton, Deborah J Thompson, Amanda B Spurdle
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 22 Issue 5 Pg. 851-61 (Oct 2015) ISSN: 1479-6821 [Electronic] England
• PMID: 26330482 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 Society for Endocrinology.

Chemical References

• Cytoskeletal Proteins
• ESR1 protein, human
• Estrogen Receptor alpha
• Nerve Tissue Proteins
• Nuclear Proteins
• SYNE1 protein, human

Topics

• Breast Neoplasms (genetics)
• Case-Control Studies
• Computational Biology
• Cytoskeletal Proteins
• Databases, Genetic
• Endometrial Neoplasms (genetics)
• Estrogen Receptor alpha (genetics)
• Female
• Genetic Loci
• Genetic Predisposition to Disease
• Genotype
• Humans
• Meta-Analysis as Topic
• Nerve Tissue Proteins (genetics)
• Nuclear Proteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Promoter Regions, Genetic (genetics)
• Risk Factors