Abstract 2752: Genetic variants in MMPs genes as predisposition factors for ovarian cancer risk and clinical outcome

Abstract

Abstract Ovarian cancer is the leading cause of death resulting from the cancer of female reproductive system. Matrix metalloproteinases (MMPs) are a family of zinc-dependent and structure related endopeptidases that have been implicated in the development and prognosis of cancers including ovarian cancer. In this case control study of 417 ovarian cancer cases and 417 healthy controls, we genotyped a comprehensive panel of 266 potential functional single nucleotide polymorphisms (SNPs) in 23 MMP genes and analyzed their associations with ovarian cancer risk, and overall survival and response to chemotherapy in ovarian cancer cases who received platinum-based chemotherapy with surgery. The analysis was further restricted to 339 Caucasian ovarian cancer cases and 349 Caucasian healthy controls to minimize potential confounding by population stratification. We observed 24 SNPs significantly associated with the risk of ovarian cancer, 4 of which remained significant after adjusting for multiple comparisons using q value at 10% level. The top 3 SNPs were from MMP20 and the most significant association was observed for SNP rs2292730 (OR = 2.03, 95% CI = 1.39 − 2.96, P = 0.0002, recessive model). We then analyzed the cumulative effect of the top four SNPs on ovarian cancer risk by counting the number of unfavorable genotypes in each individual and found a significant gene-dosage effect (P for trend < 0.0001). We applied classification and regression tree (CART) analysis to explore high order gene-gene interaction and identified 4 terminal nodes with differential risk of ovarian cancer (percentage of cases in terminal nodes ranging from 33% to 63%). In survival analysis, there were 42 SNPs significantly associated with overall survival, 34 of which remained significant after adjusting for multiple comparisons using q value at 10% level and 4 of which showed significant association with response to chemotherapy. The most significant association was observed for SNP rs2239008 from MMP1 (HR = 3.10, 95% CI = 1.54 − 6.24, P = 0.0016). We also studied the cumulative effect of the top SNPs on overall survival. Compared to low risk group of individuals with ≤ 11 unfavorable genotypes, patients with 12∼18 and ≥ 19 unfavorable genotypes had significantly increased risk of death (HR = 2.31, 95% CI = 1.51 − 3.51, and HR = 4.06, 95% CI = 2.45 − 6.73, respectively). The median survival times (MST) for patients having ≤ 11, 12∼18 and ≥ 19 unfavorable genotypes were 70.7, 40, and 25 months, respectively (log rank P < 0.0001). Survival tree analysis showed that patients can be differentiated into distinct risk groups based on their genetic profiles. There were 9 terminal nodes identified by the survival tree analysis with MSTs ranging from 18.2 to 151.7 months. In conclusion, our results suggest that genetic variants in MMP pathway genes may modulate the risk and clinical outcomes of ovarian cancer, both individually and jointly. 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 2752.