Abstract 926: Oxidative Stress Response Sequence Variants as Predictors of Prostate Cancer Risk and Aggressive Disease among men of European and African Descent

Abstract

Abstract Background: Prostate cancer (PCA) has the second incidence and mortality rates among cancers affecting U.S. men. Furthermore, men of African descent (MAD) are at increased risk to develop PCA, be diagnosed with more aggressive cases, and less likely to survive 5-years following diagnosis when compared to men of European descent (EA). Unfortunately, mechanisms contributing to PCA etiology and disparities are poorly characterized. Identification of genetic and environmental factors contributing to PCA development and disease aggressiveness are essential to reducing its incidence, disparity and mortality. Research Goal & Objective: With the ultimate goal of improving clinical management, we systematically evaluated the relationship between oxidative stress-related (OSR) susceptibility factors and PCA outcomes among a case control population of 3,200 men. Hypothesis: We hypothesized individuals inheriting variant OSR loci linked with reduced antioxidation, oxidative DNA damage repair, and apoptotic potential have an increased risk of developing PCA and aggressive disease. Materials and Methods: In order to evaluate the effects of OSR sequence variants on PCA we used SNP profile data collected from 2277 EA participants of the Cancer Genetic Markers of Susceptibility project (1176 cases, 1101 controls) and 923 MAD (224 cases, 699 controls). We evaluated the independent effects of 205 variant OSR genes in relation to PCA risk and aggressive disease using logistic regression and multi-factor dimensionality reduction (MDR) modeling. Results: Among EA, inheritance of at least one minor OSR loci involved in antioxidation [NOS2A_rs2274894, TXNDC5 rs2743993, TXNRD2_rs5746847), DNA repair (OGG1_rs12570, XRCC1_rs1799778), and apoptosis [BNIP3L_rs7813520, CASP3_rs4647693, CDK9_rs3217751, MAPK1_rs743409, MSRA (rs6997224, rs17151728), RASSF5_rs11589, TGFB2_rs1891467, TNFAIP8_rs1112247] associated with PCA risk and aggressive disease (p<0.046). We also identified three additional apoptotic variants (i.e., BCL2L11_rs3789068, CASP9_rs1052576, NFKB1_rs230528) associated with PCA risk (p<0.043) among MAD. MDR with permutation testing will be used to determine which loci remain significant after controlling for multiple comparisons. Conclusions: Our findings suggest that variations in genes involved OSR may play a role in prostate carcinogenesis among EA and MAD. Population attributable risk calculations may allow us to discern whether OSR markers may help to explain prostate cancer incidence disparities among MAD. Further analysis of gene-gene and gene-environment interactions in OSR susceptibility markers will allow us to better characterize a panel capable of predicting PCA risk and disease progression in high-risk subgroups. 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 926.