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

We conducted a meta-analysis of three endometrial cancer (EC) GWAS and two replication phases totaling 7,737 EC cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci at 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). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the intergenic 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 EC protective allele suppressed gene expression in vitro suggesting that the regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of EC.