Modifiers of Cancer Risk in BRCA 1/2 Mutation Carriers

BRCA 1/2 突变携带者癌症风险的调节因子

• 批准号: 6780089
• 负责人: TIMOTHY R REBBECK
• 金额: $ 59.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780089
• 关键词: DNA damage; DNA repair; brca gene; breast neoplasm /cancer diagnosis; breast neoplasms; cancer risk; clinical research; disease /disorder onset; family genetics; female; gene environment interaction; gene interaction; gene mutation; genetic carriers; genetic mapping; genetic markers; genetic susceptibility; genotype; human subject; neoplasm /cancer classification /staging; neoplasm /cancer epidemiology; neoplasm /cancer genetics; neoplasm /cancer site; ovary neoplasms; women' s health

DESCRIPTION (provided by applicant): Inheritance of a germline mutation in the BRCA1 or BRCA2 (BRCA1/2) genes is associated with an increased risk of developing breast and ovarian cancer. However, there is also substantial variability in the penetrance of breast cancer in BRCA1/2 mutation carriers. These observations imply that germline mutations in BRCA1/2 may be necessary to explain the Mendelian pattern of cancer in some families, but may not be sufficient to completely describe the inter-individual variability in the age-specific risk of cancer. There is substantial evidence that BRCA1/2-associated breast carcinogenesis involves the recognition and repair of DNA damage to maintain genomic integrity. The goal of this proposal is to identify genotypes involved in DNA damage recognition and repair pathways that influence BRCA 1/2-associated breast cancer risk. This proposal will be facilitated by the resources of a multidisciplinary collaborative group that has collected data on over 2,000 BRCA1/2 mutation carriers. This existing data resource provides a unique opportunity to accomplish the following specific aims. We hypothesize that in the presence of a mutated BRCA1 or BRCA2 gene, additional inherited variants that confer additional impairment to DNA damage recognition or repair will alter the penetrance of breast cancer. The goal of this proposal is to identify genotypes involved in DNA damage recognition and repair pathways that influence BRCA1/2-associated cancer risk. This proposal will be facilitated by the resources of a multidisciplinary collaborative group that has collected data on over 2,000 BRCA1/2 mutation carriers. We propose to increase the size of this cohort during the funding period and generate and epidemiologically appropriate nested study sample to accomplish the following specific aims: Specific Aim 1: To use a case-only study of BRCA1/2 mutation carriers to evaluate whether candidate genes alter the characteristics of breast tumors; Specific Aim 2: To use a nested case-control study to evaluate whether candidate genes are associated with altered breast cancer risk; Specific Aim 3: To use a nested case-control study to evaluate whether candidate genes predict cancer site (breast vs. ovarian). Knowledge about cancer risk modifiers may improve our risk assessment ability, identify relevant pathways of BRCA1/2-mediated carcinogenesis, and identify exposures that can be used to develop appropriate cancer prevention strategies. Our substantial multidisciplinary experience will therefore allow us to readily translate basic science and epidemiological data to clinically relevant information.

描述（由申请人提供）：BRCA1或BRCA2（BRCA1/2）基因中种系突变的遗传与患乳腺癌和卵巢癌的风险增加有关。但是，BRCA1/2突变载体中乳腺癌的渗透性也存在很大的差异。这些观察结果表明，BRCA1/2中的种系突变可能需要解释某些家庭的孟德尔癌癌的模式，但可能不足以完全描述特定年龄特异性癌症风险的个体间变异性。有大量证据表明，BRCA1/2相关的乳腺癌发生涉及对DNA损伤的识别和修复以维持基因组完整性。该提案的目的是确定参与DNA损伤识别的基因型和影响BRCA 1/2相关乳腺癌风险的修复途径。该提案将由多学科合作集团的资源促进，该集团收集了有关2,000多个BRCA1/2突变载体的数据。现有的数据资源为完成以下特定目标提供了独特的机会。 我们假设在存在突变的BRCA1或BRCA2基因的情况下，其他遗传变体赋予额外的损害识别DNA损伤或修复会改变乳腺癌的渗透率。该提案的目的是确定参与DNA损伤识别的基因型和影响BRCA1/2相关癌症风险的修复途径。该提案将由多学科合作集团的资源促进，该集团收集了有关2,000多个BRCA1/2突变载体的数据。我们建议在资金期间增加该队列的规模，并生成和流行病学上适当的嵌套研究样本，以实现以下特定目的：具体目的1：使用仅病例研究BRCA1/2突变载体来评估候选基因是否会改变乳腺肿瘤的特征；特定目的2：使用嵌套的病例对照研究来评估候选基因是否与乳腺癌风险改变有关；特定目的3：使用嵌套的病例对照研究来评估候选基因是否预测癌症部位（乳腺癌与卵巢）。有关癌症风险改良剂的知识可能会提高我们的风险评估能力，确定BRCA1/2介导的致癌途径的相关途径，并确定可用于制定适当预防癌症策略的暴露。因此，我们丰富的多学科经验将使我们很容易将基础科学和流行病学数据转化为临床相关信息。