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

Tracy A. O'Mara, Dylan M. Glubb, Jodie N. Painter, Timothy Cheng, Joe Dennis, 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, Shirley Hodgson, Peter A. Fasching, Alexander HeinMatthias 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, Manjeet K. Bolla, Kyriaki Michailidou, Jonathan P. Tyrer, Qin Wang, John L. Hopper, 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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)851-861
Number of pages11
JournalEndocrine-Related Cancer
Issue number5
StatePublished - Oct 1 2015


  • ESR1
  • Endometrial cancer
  • Fine-mapping analysis
  • Single-nucleotide polymorphisms

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research


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