GENETIC SUSCEPTIBILITY IN PROSTATE CANCER

DESCRIPTION (provided by applicant): Several etiologic factors have been suggested for prostate cancer, including both genetic and environmental factors. Established risk factors include age, race, and family history. It is becoming more apparent that common polymorphisms that result in quantitative or qualitative functional differences in protein products play an important role in modifying disease risk. For prostate cancer, the most compelling hypothesis for increased cancer risk supports a hormonal involvement, which could include enzymes involved in the androgen metabolic pathway and gonadotrophins. Additionally, there is evidence suggesting that estrogen metabolites, as genotoxins, also increase risk for prostate cancer. In this study, we propose to systematically test the hypothesis that common genetic polymorphisms for enzymes that catalyze the synthesis and bioactivation of androgens and estrogen (CYP11A1, CYP17, CYP 19, HSD3B2, HSD17B1, HSD17B3, AKR1C3, SRD5A2), either individually or in combination, are risk factors for prostate cancer. In addition, we hypothesize that common genetic polymorphisms that catalyze the synthesis of catecholestrogens (CYP1A1 and CYP1B1), as well as enzymes that metabolically inactivate estrogens, catecholestrogens, or genotoxins generated from catecholestrogens (COMT, SULT1A1, the GSTs and NQO1), either individually or in combination, might also represent predisposing genetic risk factors for prostate cancer. This hypothesis will be tested in a case-control study that uses two sets of previously identified cases - those with a strong family history of prostate cancer (n=449 from 181 families) and those with a reported negative prostate cancer family history (n=500) - and a population-based control group (n=510). The controls have been extensively screened for prostate cancer by digital rectal examination, serum PSA measurement, transrectal sonographic imaging and when indicated, biopsy. At the conclusion of this project, we will have provided important insight into the potential role of a group of genes important in androgen and estrogen metabolism and generated hypotheses about how these interact in the etiology of prostate cancer. Additionally, by making pairwise comparisons among these three groups of subjects, we will be able to discern whether these common polymorphisms are more strongly associated with familial or sporadic prostate cancer, similarly associated with both or with neither. The overarching goal of this project is to identify genetic susceptibility factors of prostate cancer in order to improve our understanding of the etiology of this disease and potentially identify men at increased risk of developing the disease in whom prevention strategies might be targeted.