Uncovering Breast Cancer Predisposition Factors in Puerto Rico

揭示波多黎各的乳腺癌易感因素

• 批准号: 8550011
• 负责人: Jaime L Matta
• 金额: $ 5.06万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550011
• 关键词: Accounting; BRCA1 gene; Cancer Center; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell Cycle Regulation; Collaborations; Coupled; Custom; DNA Damage; DNA Repair; DNA Repair Pathway; Data; Development; FOLH1 gene; Family; Fostering; General Population; Genes; Genetic; Genetic Predisposition to Disease; Germ Lines; Germ-Line Mutation; Hispanics; Individual; Knowledge; Libraries; Link; Malignant Neoplasms; Medicine; Mutate; Mutation; Play; Population; Predisposition; Preparation; Prevalence; Puerto Rican; Puerto Rico; Regimen; Research; Research Personnel; Risk; Role; Sampling; Screening procedure; Signal Transduction; Somatic Mutation; Surveys; Technology; Testing; Therapeutic; Treatment Efficacy; Vision; Woman; base; cancer risk; design; exome; genetic variant; high risk; improved; inhibitor/antagonist; malignant breast neoplasm; medical schools; response; tumor; tumor progression; tumorigenesis

The DNA repair pathways and the signaling networks that link DNA repair to cell cycle regulation, known as the DNA damage response (DDR), constitute a central mechanism in the development of cancer. The genes underiying DNA repair and DDR have been shown to be key players in genetic predisposition to breast cancer and subsequent tumor progression. The overall objective of the research described in this proposal is to identify the germline and somatic genetic changes in DNA damage response genes that underiie the risk of breast cancer, specifically in the population of Puerto Rico. The overall hypothesis is that the germ-line and tumor genetic factors underiying breast cancer susceptibility in Puerto Rico may differ qualitatively or quantitatively from those in Caucasian women. In specific aim #1, we will determine the prevalence of germline changes in the genes involved in breast cancer risk. We will perform a comprehensive screening of a panel 21 candidate genes that have been implicated in breast cancer predisposifion in the general population. Several of those genes are involved in the cellular response to DNA damage. We will accomplish this aim using capture technology coupled with massively parallel sequencing. We expect to determine whether the genes that were previously implicated in breast cancer predisposition are also determinants of breast cancer risk in the Puerto Rican population. In specific aim #2, we propose to determine the prevalence of somatic changes in genes involved in DNA repair and DDR. This will be accomplished by the library preparation from tumor samples and full exome capture hybridization followed by massively parallel sequencing. The identification of somatic changes in DNA repair and DDR genes is expected to reveal key genes that are mutated in tumorigenesis in the Puerto Rican population. This project proposes to examine both germline and somatic changes, thereby providing an integrated picture of the role of genetic variants in DNA repair and DDR genes in breast cancer risk and development. It targets a Hispanic population, which is often underrepresented in genetic studies. Our findings may uncover genetic changes specific to this population that will allow for the development of custom-designed predisposifion tests. Importantly, these data will serve the basis for a vision of personalized medicine that takes into account natural differences in populations to maximize the idenfification of individuals at risk and the efficacy of therapeutic regimens. This project supports the overall U54 applicafion by fostering the close collaboration between PSM and MCC investigators while gathering knowledge that will directly improve cancer prevenfion and treatment in Puerto Rico.

DNA 修复途径和将 DNA 修复与细胞周期调控联系起来的信号网络，称为 DNA损伤反应（DDR）构成了癌症发展的核心机制。基因 基础 DNA 修复和 DDR 已被证明是乳腺癌遗传易感性的关键因素 以及随后的肿瘤进展。本提案中描述的研究的总体目标是 识别 DNA 损伤反应基因的种系和体细胞遗传变化，这些变化会导致以下风险： 乳腺癌，特别是在波多黎各人群中。总体假设是种系和 波多黎各乳腺癌易感性的肿瘤遗传因素可能存在质的差异或不同 与白人女性的数量相比。在具体目标#1中，我们将确定种系的患病率 与乳腺癌风险相关的基因发生变化。我们将对小组进行全面筛选 21 与普通人群乳腺癌易感性有关的候选基因。一些 这些基因涉及细胞对 DNA 损伤的反应。我们将使用以下方式实现这一目标 捕获技术与大规模并行测序相结合。我们希望确定基因是否 以前与乳腺癌易感性有关的因素也是乳腺癌风险的决定因素 波多黎各人口。在具体目标#2中，我们建议确定以下部位体细胞变化的发生率： 参与 DNA 修复和 DDR 的基因。这将通过肿瘤的文库制备来完成 样品和全外显子组捕获杂交，然后进行大规模并行测序。鉴定 DNA 修复和 DDR 基因的体细胞变化有望揭示在 波多黎各人群的肿瘤发生。该项目建议检查种系和体细胞 变化，从而提供遗传变异在 DNA 修复和 DDR 基因中的作用的综合图景 乳腺癌风险和发展。它针对的是西班牙裔人口，而西班牙裔人口在 遗传学研究。我们的研究结果可能会揭示该人群特有的基因变化，从而使 开发定制设计的易感测试。重要的是，这些数据将为愿景奠定基础 个性化医疗考虑到人群的自然差异，以最大化 识别处于危险中的个体以及治疗方案的功效。该项目支持总体 通过促进 PSM 和 MCC 调查人员之间的密切合作来收集 U54 应用 将直接改善波多黎各癌症预防和治疗的知识。