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: 7931198
• 负责人: WANGUO LIU
• 金额: $ 20.29万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931198
• 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; 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; Pathway interactions; Penetrance; Phosphotransferases; Play; 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; population based; 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，多个基因的一些低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，DNA损伤反应途径的破坏赋予前列腺癌的易感性。事实上，我们已经证明CHK 2和p53 AIP 1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，无论是单独还是组合，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名未受影响的男性血液DNA中筛选56个记录良好的DNA损伤反应基因的非同义变体。在目标2中，我们将在一项病例对照研究中检验这些变异的显著性，该研究使用了两组先前确定的病例-具有强烈前列腺癌家族史的病例（来自189个家族的n=498）和具有阴性前列腺癌家族史的病例（n=499），以及基于人群的对照组（n=558）。对照组通过直肠指检、血清PSA测定、经直肠超声成像和（如有指征）活检进行广泛的前列腺癌筛查。在目标3中，我们将在独立的病例组和对照组中验证目标2中与家族性或散发性前列腺癌相关的变体，所述病例组和对照组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男性.在这个项目的结论，我们将提供重要的见解，一组基因的潜在作用，重要的DNA损伤反应和产生的假设，这些基因如何相互作用，在前列腺癌的病因。此外，通过在这三组受试者之间进行成对比较，我们将能够辨别这些遗传变异是否与家族性或散发性前列腺癌更密切相关，与两者或两者都不相关。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病因的了解，并提供工具，用于潜在识别可能成为预防策略目标的患该疾病风险增加的男性。