DNA Damage-Response Defects in Prostate Cancer Risk

DNA 损伤反应缺陷与前列腺癌风险的关系

• 批准号: 7502688
• 负责人: WANGUO LIU
• 金额: $ 31.24万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-29 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502688
• 关键词: Age; Alleles; Apoptosis; Area; BRCA1 gene; Biopsy; Blood; CHEK2 gene; Cancer Family; Cancer Patient; Candidate Disease Gene; Case-Control Studies; Classification; Complex; Consult; Control Groups; Country; DNA; DNA Damage; Data; Databases; Defect; Digital Rectal Examination; Disease; Disruption; Etiology; Family; Family history of; Frameshift Mutation; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genome Stability; Genotype; Germ-Line Mutation; Goals; Hereditary Disease; High Pressure Liquid Chromatography; Human; Image; Leukocytes; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Methods; Mutate; Mutation; Neoplastic Cell Transformation; Numbers; Pathway interactions; Penetrance; Phosphotransferases; Play; Population; Predisposition; Prevention; Prevention strategy; Proteins; Race; Reporting; Research Personnel; Risk; Risk Factors; Risk Marker; Role; Sampling; Screening for Prostate Cancer; TP53 gene; Technology; Testing; Time; Universities; Variant; base; cancer risk; case control; clinically significant; genetic linkage analysis; genetic risk factor; genetic variant; improved; insight; male; men; mutant; mutation carrier; novel; peripheral blood; programs; response; serum PSA; success; tool; tumorigenesis

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.

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中起着重要作用。然而，这种疾病背后的遗传基础仍然知之甚少。越来越明显的是，多个基因的一些低外显性等位基因的遗传变异可能会导致前列腺癌的风险。此外，越来越多的证据表明，破坏DNA损伤反应途径会增加前列腺癌的易感性。事实上，我们已经证明了Chk2和p53AIP1的胚系突变降低了它们对DNA损伤和前列腺癌风险增加的反应能力，但还需要更全面和系统的研究。在这项研究中，我们建议系统地检验这一假设，即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。在目标1中，我们将从94名前列腺癌患者和94名未受影响的男性中筛选出血液DNA中非同义变异的56个有充分证据的DNA损伤反应基因。在目标2中，我们将在一项病例对照研究中测试这些变异的重要性，该研究使用了两组以前确定的病例-那些有强烈前列腺癌家族史的病例(189个家族中的498人)和那些报告的前列腺癌家族史阴性的人(n=499)，以及基于人群的控制组(n=558)。对照组已经通过直肠指检、血清PSA测量、经直肠超声成像以及在需要的情况下通过活检进行前列腺癌的广泛筛查。在目标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，这些病例和对照包括在约翰·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名年龄匹配的未受影响的对照组男性。在本项目结束时，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，并产生关于这些基因如何在前列腺癌病因中相互作用的假设。此外，通过在这三组受试者之间进行配对比较，我们将能够辨别这些基因变异与家族性或散发性前列腺癌的相关性更强，两者都类似，还是两者都不相关。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的了解，并为潜在地识别可能有针对性地采取预防策略的罹患前列腺癌风险较高的男性提供工具。