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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. OR per-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.

plos genetics

Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”