MOLECULAR EPIDEMIOLOGY OF PROSTATE CANCER

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 背景：引起前列腺癌的遗传和环境因素还不清楚。本研究旨在寻找遗传毒性应激反应的表型和基因型标记中的危险因素。彗星试验和诱变剂敏感性评价了短期培养的人淋巴细胞对DNA损伤（如博莱霉素暴露）的反应。这两种检测方法都是越来越受欢迎的DNA损伤和修复的测量方法，用作包括肺癌，乳腺癌和结肠癌在内的几种癌症的风险标志物。高DNA损伤（彗星试验中的尾矩或诱变剂敏感性中的染色单体断裂）和低DNA修复率与某些癌症的风险增加相关。由于尚未研究前列腺癌，因此本研究将评价彗星试验和诱变剂敏感性作为前列腺癌风险的指标。细胞凋亡是消除不能正确修复DNA损伤的细胞的一种方法。我们推测，在短期培养的淋巴细胞中，博来霉素暴露引起的低凋亡反应表明癌症风险增加。此外，我们将研究这些表型措施在白色血细胞与肿瘤组织中的p53肿瘤抑制基因的突变。p53基因保护细胞免受致癌变化的影响，并且在前列腺癌中经常发生突变。预计对遗传毒性应激反应不足与某些p53突变的高频率相关。DNA修复能力降低的遗传变异先前与前列腺癌风险相关。将检查OGG 1和XRCC 1中这些遗传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。 假设：我们的假设是，前列腺癌的风险与个体间对遗传毒性应激反应的差异有关。 具体目标：本研究有两个主要目标。目标1。建立前列腺癌研究的数据和组织库目标2.使用储存库来确定对DNA损伤的反应能力降低是否与前列腺癌风险增加相关。 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。将获得流行病学数据、临床数据和血液、口腔细胞、唾液、尿液、指甲剪和肿瘤组织样本，并检查前列腺癌遗传易感性标志物。短期培养白色血细胞，以检测对DNA损伤的反应（彗星试验、诱变剂敏感性和细胞凋亡），并从各种标本中提取DNA和其他生物分子，以评价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。 重要性：这项试点研究有望填补我们对前列腺癌病因学理解的重要空白，确定前列腺癌风险的遗传修饰因子，提出新的假设来关注前列腺癌预防，并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.