DNA Damage-Response Defects in Prostate Cancer Risk

描述（由申请人提供）：有大量证据表明遗传学在前列腺癌的病因学中起重要作用。然而，这种疾病的遗传基础仍然知之甚少。越来越明显的是，多种基因的一些低外显率等位基因的遗传变异可能导致前列腺癌的风险。此外，越来越多的证据表明，DNA损伤反应途径的破坏与前列腺癌的易感性有关。事实上，我们已经证明CHK2和p53AIP1的种系突变降低了它们对DNA损伤的反应能力，增加了前列腺癌的风险，但还需要更全面和系统的研究。在这项研究中，我们建议系统地测试DNA损伤反应途径基因中罕见或常见的遗传变异，无论是单独的还是联合的，都是前列腺癌的危险因素。在Aim 1中，我们将筛选来自94名前列腺癌患者和94名未受影响男性的血液DNA中56个记录良好的DNA损伤反应基因的非同义变异。在Aim 2中，我们将在一项病例对照研究中测试这些变异的意义，该研究使用两组先前确定的病例-具有强烈前列腺癌家族史的患者（n=498来自189个家庭）和报告为阴性前列腺癌家族史的患者（n=499），以及基于人群的对照组（n=558）。对照组通过直肠指诊、血清PSA测量、经直肠超声成像以及指征时活检广泛筛查前列腺癌。在Aim 3中，我们将在一组独立的病例和对照中验证Aim 2中与家族性或散发性前列腺癌相关的变异，包括在约翰霍普金斯大学收集的734例家族性病例、462例散发性病例和500例年龄匹配的未受影响的对照男性。在这个项目结束时，我们将对一组在DNA损伤反应中重要的基因的潜在作用提供重要的见解，并对这些基因如何在前列腺癌的病因学中相互作用产生假设。此外，通过对这三组受试者进行两两比较，我们将能够辨别这些基因变异与家族性前列腺癌或散发性前列腺癌的相关性是否更强，与两者的相关性是否相似。该项目的最终目标是确定前列腺癌的遗传风险因素，以提高我们对这种疾病的病因学的理解，并为潜在识别患这种疾病风险增加的男性提供工具，这些男性可能成为预防策略的目标。

DESCRIPTION (provided by applicant): There is substantial evidence that genetics plays an important role in the etiology of prostate cancer. However, the genetic basis underlying this disease remains poorly understood. It is becoming more apparent that genetic variants in a number of low-penetrance alleles of multiple genes may contribute to prostate cancer risk. Additionally, a growing body of evidence suggests that disruption of the DNA damage-response pathway confer susceptibility to prostate cancer. Indeed, we have demonstrated that germline mutations in CHK2 and p53AIP1 diminish their capacities to respond to DNA damage and increased prostate cancer risk, but more comprehensive and systematic studies are needed. In this study, we propose to systematically test the hypothesis that rare or common genetic variants in the DNA damage-response pathway genes, either individually or in combination, are risk factors for prostate cancer. In Aim 1, we will screen 56 well-documented DNA damage-response genes for non-synonymous variants in blood DNA from 94 prostate cancer patients and 94 unaffected men. In Aim 2, we will test the significance of these variants in a case-control study that uses two sets of previously identified cases - those with a strong family history of prostate cancer (n=498 from 189 families) and those with a reported negative prostate cancer family history (n=499), and a population-based control group (n=558). The controls have been extensively screened for prostate cancer by digital rectal examination, serum PSA measurement, transrectal sonographic imaging, and when indicated, by biopsy. In Aim 3, we will validate the variants in Aim 2 that are associated with either familial or sporadic prostate cancer in an independent sets of cases and controls including 734 familial cases, 462 sporadic cases, and 500 age- matched unaffected control men collected at Johns Hopkins University. At the conclusion of this project, we will have provided important insights into the potential role of a group of genes important in DNA damage-response and generated hypotheses as to how these genes interact with each other 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 genetic variants are more strongly associated with familial or sporadic prostate cancer, similarly associated with both or with neither. The ultimate goal of this project is to identify genetic risk factors of prostate cancer in order to improve our understanding of the etiology of this disease and to provide tools for potential identification of men at increased risk of developing the disease in whom prevention strategies might be targeted.