Johnatty, Sharon E.

Abstract Introduction: Alterations in components of the stromal tissue that underlie the epithelium can initiate, promote or inhibit epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) are stromal genes with reduced expression in serous ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) in these genes may influence susceptibility to serous ovarian cancer. Methods: To test this hypothesis, we compared genotype frequencies of 11 tagSNPs in DCN and LUM between 397 Caucasian cases with primary serous ovarian cancer and 920 Caucasian controls in two studies conducted at Mayo Clinic and Duke University (discovery set). Associations were evaluated further in a third Caucasian population of 436 cases and 1,098 controls in Australia (replication set). TagSNPs were selected from unrelated Caucasian samples within HapMap based on the following criteria: (i) minor allele frequency ≥ 0.05, (ii) pairwise linkage disequilibrium (LD) of r2 ≥ 0.8, and (iii) location within, and 5kb upstream and downstream of, each gene region. Genotyping was performed using the Illumina GoldenGate™ assay and associations between SNPs and serous cancer were evaluated using unconditional logistic regression to estimate per allele odds ratios (OR) and 95% confidence intervals (95%CI). Untyped genotypes for DCN rs13312816 in the discovery set, and for DCN rs3138165 and LUM rs17018765 in the replication set, were imputed using the MACH software. Results: In the discovery set, we observed inverse associations between DCN rs3138165 (OR=0.7; 95%CI=0.5-1.0), DCN rs13312816 (OR=0.7; 95%CI=0.5-1.0), DCN rs516115 (OR=0.8; 95%CI=0.7-1.0) and LUM rs17018765 (OR=0.7; 95%CI=0.5-1.0) and risk of serous ovarian cancers (all Ptrend=0.06). Associations were confirmed in the replication set for DCN rs3138165 (OR=0.6; 95%CI=0.4-0.9; Ptrend=0.009), DCN rs13312816 (OR=0.7; 95%CI=0.5-0.9; Ptrend=0.01) and LUM rs17018765 (OR=0.6; 95%CI=0.4-0.9; Ptrend=0.008), but not for DCN rs516115 (Ptrend=0.20). To increase statistical power, data from the discovery and replication sets were combined (833 cases and 2,013 controls) following confirmation of no statistical heterogeneity in the ORs between study sites. In the combined sample, associations were strengthened for DCN rs3138165 (OR=0.7; 95%CI=0.5-0.9; Ptrend=0.002), DCN rs13312816 (OR=0.7; 95%CI=0.5-0.9; Ptrend=0.002), DCN rs516115 (OR=0.9; 95%CI=0.8-1.0; Ptrend=0.03) and LUM rs17018765 (OR=0.6; 95%CI=0.5-0.8; Ptrend=0.001). All four SNPs were in the same LD block on chromosome 12, suggesting that serous ovarian cancer susceptibility may be driven by a single, correlated variant in the region. Conclusion: The findings of this study suggest that genetic variation in DCN and LUM may influence susceptibility to serous ovarian cancer and contribute to the mounting evidence that supports the role of the stroma in epithelial ovarian cancer. 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 2854.

Abstract There is increasing evidence that neighboring stromal cells are not uninvolved bystanders in the pathway to cancer. We hypothesized that SNPs in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to ovarian cancer susceptibility. We therefore used a two-stage approach to comprehensively evaluate common single nucleotide polymorphisms (SNPs) in the Ovarian Cancer Association Consortium (OCAC) for 173 genes involved in stromal-epithelial interactions. Cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1536 SNPs using an Illumina GoldenGate™ BeadArray array. Logistic regression was used to estimate odds ratios (ORs) and adjust for potential confounders. Based on Positive Predictive Value estimates, three SNPs - PODXL rs1013368, ITGA6 rs13027811 and MMP3 rs522616 - were selected for replication using TaqMan genotyping in 3,734 serous invasive cases and 10,067 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele <0.05 in the test set, and which fitted into an iPLEX design, were selected for replication by a subset of five OCAC studies (n=1771 serous invasive cases; n=4022 controls). The associations observed in the test set for the PODXL, ITGA6 and MMP3 SNPs were completely attenuated in the replication set (adj. Pper-allele ≥0.5). However, TERT rs7726159 showed evidence of a log additive association with ovarian cancer risk in the replication study (Pper-allele =0.03). Combined analysis of the test and replication sets for this SNP showed a significant association with risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04 - 1.24) p = 0.003]. A stronger association was observed for serous invasive cases when data for all ethnicities were included [adj. ORper-allele 1.18 (1.09 - 1.28) p = 2.46 × 10−5]. Stratification by histological subtype and malignant potential showed that TERT rs7726159 was also associated with risk of serous borderline tumors, but not with any other subtypes. Although TERT variants have not been previously reported to be associated with ovarian cancer, multiple genome-wide association studies have reported associations with this locus and risk of glioma, basal cell carcinoma, and several cancer types that are known to originate in the epithelium, including lung, bladder, prostate and cervical cancer. Further analysis of this locus is necessary to definitively identify the causal SNP(s). Our study adds to the growing evidence that, as well as 8q24, the TERT locus at 5p15.33, is a general cancer susceptibility locus. 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 4727.