Five endometrial cancer risk loci identified through genome-wide association analysis.
Cheng TH., Thompson DJ., O'Mara TA., Painter JN., Glubb DM., Flach S., Lewis A., French JD., Freeman-Mills L., Church D., Gorman M., Martin L., National Study of Endometrial Cancer Genetics Group (NSECG) None., Hodgson S., Webb PM., Australian National Endometrial Cancer Study Group (ANECS) None., Attia J., Holliday EG., McEvoy M., Scott RJ., Henders AK., Martin NG., Montgomery GW., Nyholt DR., Ahmed S., Healey CS., Shah M., Dennis J., Fasching PA., Beckmann MW., Hein A., Ekici AB., Hall P., Czene K., Darabi H., Li J., Dörk T., Dürst M., Hillemanns P., Runnebaum I., Amant F., Schrauwen S., Zhao H., Lambrechts D., Depreeuw J., Dowdy SC., Goode EL., Fridley BL., Winham SJ., Njølstad TS., Salvesen HB., Trovik J., Werner HM., Ashton K., Otton G., Proietto T., Liu T., Mints M., Tham E., RENDOCAS None., Consortium C., Jun Li M., Yip SH., Wang J., Bolla MK., Michailidou K., Wang Q., Tyrer JP., Dunlop M., Houlston R., Palles C., 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., Cunningham JM., Pharoah PDP., Dunning AM., Edwards SL., Easton DF., Tomlinson I., Spurdle AB.
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.