Evidence from twin and family studies suggests an inherited genetic component to epithelial ovarian cancer (EOC) risk. Rare, high-penetrance alleles of genes such as BRCA1 and BRCA2 account for about 40% of excess familial risk, and GWAS have recently identified common risk alleles at 9p22, 8q24, 2q31 and 19p13, with two additional loci at 3q25 and 17q21 that approached genome-wide significance. However these alleles only explain 4% of excess familial risk, and more risk loci probably exist.
A study group therefore recently pooled the data from two GWAS to inform the selection of SNPs for a large-scale replication. The North American study comprised 4 independent case-control studies that included 1,952 cases and 2,052 controls. The second study was a 2-phase multicenter GWAS that included 1,817 cases and 2,354 controls in the first phase and 4,162 cases and 4,810 controls in the second phase.
The researchers carried out a fixed-effects meta-analysis from the two GWAS for ~2.5 million genotyped or imputed SNPs. They selected 24,551 SNPs associated with the risk of either all-histology (11,647 SNPs) or serous (12,904 SNPs) ovarian cancer on the basis of ranked P values. They designed assays for 23,239 SNPs and included them on a custom Illumina Infinium iSelect array (iCOGS) comprising 211,155 SNPs designed by the Collaborative Oncological Gene-environment Study (COGS) to evaluate genetic variants for association with risk of breast, ovarian and prostate cancers. They then genotyped these SNPs in cases and controls from 43 individual studies from the Ovarian Cancer Association Consortium (OCAC) that were grouped into 34 case-control strata. These included most of the samples genotyped in the initial GWAS. An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Via Dr. Stefan Gruenwald