MOLECULAR EPIDEMIOLOGY OF PROSTATE CANCER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。背景：导致前列腺癌的遗传和环境因素尚不清楚。本研究旨在寻找基因毒性应激反应的表型和基因型标记中的危险因素。彗星试验和诱变原敏感性评估短期培养的人淋巴细胞对DNA损伤（如博来霉素暴露）的反应。这两种检测方法都是一种越来越受欢迎的DNA损伤和修复测量方法，被用作肺癌、乳腺癌和结肠癌等几种癌症的风险标记。高DNA损伤（彗星试验中的尾巴时刻或诱变原敏感性中的染色单体断裂）和低DNA修复率与某些癌症风险增加相关。由于前列腺癌尚未被研究，本研究将评估彗星试验和诱变原敏感性作为前列腺癌风险的衡量标准。程序性细胞死亡（细胞凋亡）是消除不能正确修复DNA损伤的细胞的一种方法。我们假设，短期培养淋巴细胞对博来霉素暴露的低凋亡反应表明癌症风险增加。此外，我们将研究白细胞中的这些表型测量如何与肿瘤组织中p53肿瘤抑制基因的突变相关。p53基因保护细胞不发生癌变，在前列腺癌中经常发生突变。预计对基因毒性应激反应不足与某些p53突变的高频率有关。DNA修复能力下降的基因变异先前与前列腺癌风险有关。OGG1和XRCC1基因变异与前列腺肿瘤组织中DNA损伤/修复、细胞凋亡和p53突变的相关性将被研究。假设：我们的假设是前列腺癌风险与基因毒性应激反应的个体间差异有关。具体目的：本研究有两个主要目标。目的1。建立前列腺癌研究的数据和组织库。使用该数据库来确定对DNA损伤的反应能力下降是否与前列腺癌风险增加有关。研究设计：病例对照研究将评估300例前列腺癌病例和300例年龄、性别和种族匹配的非癌症对照。将获得流行病学资料、临床资料以及血液、口腔细胞、唾液、尿液、指甲盖和肿瘤组织的样本，并检查前列腺癌遗传易感性的标志物。白细胞将进行短期培养，以测试对DNA损伤的反应（彗星试验、诱变原敏感性和细胞凋亡），并从各种标本中提取DNA和其他生物分子，以评估DNA修复基因的遗传变异、p53肿瘤抑制基因的突变和其他癌症易感性标志物。意义：本初步研究有望填补我们对前列腺癌病因学认识的重要空白，确定前列腺癌风险的遗传修饰因子，提出新的假设，关注前列腺癌的预防，帮助设计更好的癌症预防策略。

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.