Uncovering Breast Cancer Predisposition Factors in Puerto Rico

DNA修复途径和将DNA修复与细胞周期调节联系起来的信号网络，称为 DNA损伤反应(DDR)是肿瘤发生发展的核心机制。基因 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 确定DNA损伤反应基因的种系和体细胞遗传变化 乳腺癌，特别是在波多黎各的人口中。总体假设是生殖系和 波多黎各乳腺癌易感性的肿瘤遗传因素可能在性质上或 从数量上讲，与高加索女性的差异不大。在具体目标1中，我们将确定生殖系的流行率 乳腺癌风险相关基因的变化。我们将对21个小组进行全面的筛选 在普通人群中与乳腺癌易感性有关的候选基因。几个 其中的基因与细胞对DNA损伤的反应有关。我们将通过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。我们希望能确定这些基因是否 以前被认为与乳腺癌易感性有关的基因也是乳腺癌风险的决定因素 波多黎各人。在特定的目标2中，我们建议确定躯体变化的流行率 参与DNA修复和DDR的基因。这将通过从肿瘤中制备文库来实现 样本和完全外显子组捕获杂交，然后大规模平行测序。身份的鉴定 DNA修复和DDR基因的体细胞变化有望揭示突变的关键基因 波多黎各人口中的肿瘤发生。该项目建议同时检测生殖系和体细胞。 变化，从而提供了遗传变异在DNA修复和DDR基因中的作用的综合图景 在乳腺癌的风险和发展方面。它的目标是西班牙裔人口，他们在 基因研究。我们的发现可能会揭示这一群体特有的基因变化，这将允许 开发定制设计的前置处理测试。重要的是，这些数据将为远景奠定基础 考虑到人群的自然差异以最大限度地提高 识别处于危险中的个人和治疗方案的有效性。该项目总体上支持 U54应用，促进PSM和MCC调查人员在收集的同时密切合作 这些知识将直接改善波多黎各的癌症预防和治疗。

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.