Abstract
We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P per-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. P per-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (P per-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.
Highlights
Ovarian cancer is the seventh leading cause of cancer mortality among women globally, accounting for 4.2% of cancer deaths [1], due in part to the lack of practical screening methods and detectable symptoms in the early stages of tumor progression [2]
We report the findings from a large-scale analysis of common variation in genes that are expressed as a consequence of interactions between ovarian cancer cells and their host micro-environment that could influence serous ovarian cancer risk
We evaluated 1,302 common variants within or near 173 genes in two large case-control studies from the Ovarian Cancer Association Consortium (OCAC) and selected three variants for further evaluation in sixteen OCAC studies and an additional 18 for evaluation in five OCAC studies
Summary
Ovarian cancer is the seventh leading cause of cancer mortality among women globally, accounting for 4.2% of cancer deaths [1], due in part to the lack of practical screening methods and detectable symptoms in the early stages of tumor progression [2]. The aetiology of ovarian cancer has not been fully elucidated, it is generally agreed that family history of ovarian or breast cancer is the most important risk factor for epithelial ovarian cancer [3]. Given that only 3% to 5% of ovarian cancer cases present from high-risk families and residual family history associations [2], it is likely that several low-penetrance genes with relatively common alleles that confer slightly increased risk may account for a portion of the risk of non-familial ovarian cancer. The Ovarian Cancer Association Consortium (OCAC) was established in 2005 to provide a forum for the identification and validation of common low-penetrance ovarian cancer susceptibility polymorphisms with increased power [6]. OCAC recently conducted a genome-wide association study (GWAS) and identified the first susceptibility locus associated with invasive ovarian cancer risk [7]
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