Modifiers of Cancer Risk in BRCA 1/2 Mutation Carriers

描述（由申请人提供）：BRCA 1或BRCA 2（BRCA 1/2）基因的生殖系突变遗传与乳腺癌和卵巢癌风险增加相关。然而，BRCA 1/2突变携带者的乳腺癌发病率也存在很大的差异。这些观察结果表明，BRCA 1/2的生殖系突变可能是解释某些家族中孟德尔癌症模式所必需的，但可能不足以完全描述年龄特异性癌症风险的个体间差异。有大量证据表明，BRCA 1/2相关的乳腺癌发生涉及识别和修复DNA损伤，以保持基因组的完整性。该提案的目标是识别参与DNA损伤识别和修复途径的基因型，这些途径影响BRCA 1/2相关的乳腺癌风险。这项提案将得到一个多学科合作小组的资源的推动，该小组收集了2,000多名BRCA 1/2突变携带者的数据。这一现有数据资源为实现以下具体目标提供了独特的机会。 我们假设，在突变的BRCA 1或BRCA 2基因存在的情况下，额外的遗传变异，赋予额外的损害DNA损伤识别或修复将改变乳腺癌的发病率。该提案的目标是确定影响BRCA 1/2相关癌症风险的DNA损伤识别和修复途径的基因型。这项提案将得到一个多学科合作小组的资源的推动，该小组收集了2,000多名BRCA 1/2突变携带者的数据。我们建议在资助期间增加该队列的规模，并产生流行病学上适当的嵌套研究样本，以实现以下特定目标：特定目标1：使用BRCA 1/2突变携带者的仅病例研究来评估候选基因是否改变乳腺肿瘤的特征;特定目标2：使用巢式病例对照研究评估候选基因是否与乳腺癌风险改变相关;具体目标3：使用巢式病例对照研究评估候选基因是否预测癌症部位（乳腺与卵巢）。了解癌症风险修饰因子可以提高我们的风险评估能力，识别BRCA 1/2介导的致癌作用的相关途径，并识别可用于制定适当的癌症预防策略的暴露。因此，我们丰富的多学科经验将使我们能够随时将基础科学和流行病学数据转化为临床相关信息。

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.