Five endometrial cancer risk loci identified through genome-wide association analysis

Timothy H T Cheng, Deborah J Thompson, Tracy A O'Mara, Jodie N Painter, Dylan M Glubb, Susanne Flach, Annabelle Lewis, Juliet D French, Luke Freeman-Mills, David Church, Maggie Gorman, Lynn Martin, National Study of Endometrial Cancer Genetics Group (NSECG), Shirley Hodgson, Penelope M Webb, The Australian National Endometrial Cancer Study Group (ANECS), John Attia, Elizabeth G Holliday, Mark McEvoy, Rodney J ScottAnjali K Henders, Nicholas G Martin, Grant W Montgomery, Dale R Nyholt, Shahana Ahmed, Catherine S Healey, Mitul Shah, Joe Dennis, Peter A Fasching, Matthias W Beckmann, Alexander Hein, Arif B Ekici, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo Runnebaum, Frederic Amant, Stefanie Schrauwen, Hui Zhao, Diether Lambrechts, Jeroen Depreeuw, Sean C Dowdy, Ellen L Goode, Brooke L Fridley, Stacey J Winham, Tormund S Njølstad, CHIBCHA Consortium, RENDOCAS, AOCS Study Group, Malcolm Dunlop, Ian Tomlinson

Research output: Contribution to journalArticlepeer-review


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 r2 = 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.

Original languageEnglish
Pages (from-to)667-674
Number of pages8
JournalNature Genetics
Issue number6
Early online date2 May 2016
Publication statusPublished - Jun 2016


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