IDENTIFICATION AND MOLECULAR CHARACTERIZATION OF A NEW OVARIAN CANCER SUSCEPTIBILITY LOCUS AT 17q21.31

In this study, we describe a GWAS involving 18k ovarian cancer cases and 26k control patients. However, what is different from our prior case/control studies is that we chose to focus on a specific class of key regulatory genes called micro-RNAs, or miR for short. We report several variants in miRs at the 17q21.31 locus as well as novel association of nearby genes ARHGAP27 and PLEKHM1 with ovarian cancer.

Abstract

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

23535648.png