Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot"

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 Pper-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. Pper-allele>or=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-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.

Figure 1. Histology-specific adjusted per allele risk estimates for rs7726159 for all ethnicities.

Lines indicate 95% confidence intervals; bolded ORs and 95% CIs indicate statistically significant estimates (P<0.05); size of the solid box is the proportionate sample size for each histology sub-group with genotype data.

Figure 2. Gene map and LD plot of TERT-CLPTM1L locus and associated SNPs.

Colour scheme is based on r² values in Haploview; white r² = 0; shades of grey 0<r²<1; black r² = 1. Block definition is based on the method of Gabriel et al . (A) Gene map of SNPs genotyped in the discovery stage (underlined) relative to other TERT SNPs associated with cancer phenotypes (inset) and LD plot based on HapMap CEU samples. (B) Haploview plot of all TERT SNPs genotyped in 1,047 non-Hispanic White controls in our study; numbers in squares are pairwise r² values between SNPs.