Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.
O'Mara TA., Glubb DM., Painter JN., Cheng T., Dennis J., Australian National Endometrial Cancer Study Group (ANECS) None., Attia J., Holliday EG., McEvoy M., Scott RJ., Ashton K., Proietto T., Otton G., Shah M., Ahmed S., Healey CS., Gorman M., Martin L., National Study of Endometrial Cancer Genetics Group (NSECG) None., Hodgson S., Fasching PA., Hein A., Beckmann MW., Ekici AB., Hall P., Czene K., Darabi H., Li J., Dürst M., Runnebaum I., Hillemanns P., Dörk T., Lambrechts D., Depreeuw J., Annibali D., Amant F., Zhao H., Goode EL., Dowdy SC., Fridley BL., Winham SJ., Salvesen HB., Njølstad TS., Trovik J., Werner HMJ., Tham E., Liu T., Mints M., RENDOCAS None., Bolla MK., Michailidou K., Tyrer JP., Wang Q., Hopper JL., AOCS Group None., Peto J., Swerdlow AJ., Burwinkel B., Brenner H., Meindl A., Brauch H., Lindblom A., Chang-Claude J., Couch FJ., Giles GG., Kristensen VN., Cox A., Pharoah PDP., Dunning AM., Tomlinson I., Easton DF., Thompson DJ., Spurdle AB.
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.