Abstract 4729: A genome-wide association study of ovarian cancer prognosis identifies a novel locus for aggressive serous cancer on 19p13
Authors: Bolton Kelly L. , Tyrer Jonathan , Song Honglin , Ramus Susan , Jones Chris , Notaridou Maria , Chanock Stephen J. , Garcia-Closas Montserrat , Chenevix-Trench Georgia , Gayther Simon , Pharoah Paul DP ,   Ovarian Cancer Association Consortium.
Published: February 2011

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological cancer in the UK and improved understanding of the mechanisms driving prognosis is greatly needed. There is evidence that inherited genetic variation influences EOC survival but no common variants have been definitively identified to date. The aim of our study was to detect polymorphisms that influence EOC prognosis using a genome wide approach.

Subjects were from a recently completed genome-wide association study (GWAS) for genetic susceptibility to EOC. We tested 507,094 SNPs genotyped in 1,817 invasive EOC cases from the UK for association with survival using Cox proportional hazards regression (Stage 1). The 4,649 SNPs showing the strongest association with survival were genotyped in an additional 3,709 EOC cases with survival time data and 4,809 controls (Stage 2).

Based on the combined analysis of Stage 1 and 2 data, no SNP showed association with survival at genome-wide significance (P&lt;10−8). However, rs8170 on 19p13 showed a strong association with risk of serous EOC (Ptrend = 1.0×10−7) and evidence of association with overall survival (Ptrend = 1.8×10−5). This SNP and an additional disease-associated variant in the same region (rs2363956) were genotyped in an additional 4,043 EOC cases and 5,951 controls (Stage 3). The combined analysis confirmed the association with risk of serous cancer (combined data odds ratio = 1.17 95% CI 1.11 - 1.22, Ptrend = 2.9 × 10−11). There was no evidence of association with non-serous EOC risk (Ptrend = 0.76). Of the stage 3 cases, 1,845 had survival time data available. The addition of these samples provided some support for the survival association (combined data hazard ratio =1.16 95% CI 1.08 - 1.23, Ptrend = 1.6 × 10−5). The effect on survival was not attenuated by adjusting for histopathological subtype suggesting that this association is not solely a consequence of predisposition to serous disease.

These two SNPs are in two separate genes on 19p13 - MERIT40 and ANKLE2. MERIT40 is a functionally important component of the BRCA1 complex. CGH microarray data on 102 primary EOCs showed the 19p13 region to be amplified in 40% of tumors. We also found MERIT40 to show significantly higher expression levels in EOC cell lines (n=23) compared to normal ovarian epithelial cells (n=48) (P=5.6×10−9), but the genotypes of neither SNP were significantly correlated with MERIT40 expression. We are currently performing chemosensitivity assays to characterize the impact of MERIT40 on response to platinum-based chemotherapy, the first-line agent for EOC.

While we have strong evidence of an association between 19p13 and serous EOC risk, the association with survival requires confirmation in additional cases, an effort which is currently underway. Nevertheless, the detection of this biologically compelling locus may lead to the development of novel treatments for this lethal disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4729.