MOLECULAR EPIDEMIOLOGY OF PROSTATE CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Genetic and environmental factors causing prostate cancer are not well understood. This study is designed to search for risk factors among phenotypic and genotypic markers of response to genotoxic stress. Comet assay and mutagen sensitivity evaluate response to DNA damage (e.g. bleomycin exposure) in short-term cultured human lymphocytes. Both assays are an increasingly popular measure of DNA damage and repair used as a marker of risk in several cancers including lung, breast, and colon. High DNA damage (tail moment in comet assay or chromatid breaks in mutagen sensitivity) and low rate of DNA repair correlate with increased risk of certain cancers. As prostate cancer was as yet not studied, this study will evaluate comet assay and mutagen sensitivity as measures of prostate cancer risk. Programed cell death (apoptosis) is one way to eliminate cells that did not repair correctly DNA damage. We hypothesize that low apoptotic response to bleomycin exposure in the short-term cultured lymphocytes is indicative of increased cancer risk. In addition we will examine how these phenotypic measures in white blood cells correlate with mutations of the p53 tumor suppressor gene in the tumor tissue. The p53 gene guards cells from carcinogenic changes and is often mutated in prostate cancer. It is expected that insufficient response to genotoxic stress correlates with high frequency of some p53 mutations. Genetic variants with decreased DNA repair capacity were previously associated with prostate cancer risk. Correlation of these genetic variants in OGG1 and XRCC1 with DNA damage/repair, apoptosis, and p53 mutations in prostate tumor tissue will be examined. Hypothesis: Our hypothesis is that prostate cancer risk is related to interindividual variability in the response to genotoxic stress. Specific Aims: This study has two major goals. Aim 1. Establish a data and tissue repository for studies of prostate cancer Aim 2. Use the repository to determine whether decreased ability to respond to DNA damage correlates with increased prostate cancer risk. Study Design: The case-control study will evaluate 300 prostate cancer cases and 300 non-cancer controls matched on age, gender, and race. Epidemiological data, clinical data, and samples of blood, buccal cells, saliva, urine, naail clipping and tumor tissue will be obtained and examined for markers of genetic susceptibiltity to prostate cancer. White blood cells will be cultured for a short term to test response to DNA damage (comet assay, mutagen sensitivity and apoptosis) and DNA and other biomolecules will be extracted from the various specimen to evaluate genetic variants in DNA repair genes, mutations in the p53 tumor suppresor gens, and other markers of cancer susceptibility. Significance: This pilot study is expected to fill important gaps in our understanding of prostate cancer etiology, identify genetic modifiers of prostate cancer risk, produce new hypotheses to focus prostate cancer prevention, and help design better cancer prevention strategies.