Uncovering Breast Cancer Predisposition Factors 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）是肿瘤发生发展的重要机制。的基因 DNA修复和DDR是乳腺癌遗传易感性的关键因素 以及随后的肿瘤进展。本提案所述研究的总体目标是 确定DNA损伤反应基因中的种系和体细胞遗传变化，这些变化是导致 乳腺癌，特别是在波多黎各的人口中。总的假设是，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不同， 在数量上与白人女性不同。在具体目标#1中，我们将确定生殖系 与乳腺癌风险有关的基因的变化。我们将对21个小组进行全面筛查 在一般人群中与乳腺癌易感性有关的候选基因。几 这些基因中的一个参与了细胞对DNA损伤的反应。我们将通过以下方式实现这一目标： 捕获技术结合大规模平行测序。我们希望确定基因是否 以前与乳腺癌易感性有关的基因也是乳腺癌风险的决定因素， 波多黎各人口。在具体的目标#2中，我们建议确定以下患者的体细胞变化的患病率： 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 样品和全外显子组捕获杂交，然后进行大规模平行测序。的识别 DNA修复和DDR基因中的体细胞变化有望揭示在细胞内发生突变的关键基因。 波多黎各人的肿瘤发生率。这个项目建议检查生殖细胞和体细胞 变化，从而提供了DNA修复和DDR基因中遗传变异的作用的综合图片 乳腺癌的风险和发展。它的目标是西班牙裔人口，这往往是代表性不足， 基因研究。我们的研究结果可能会揭示这一人群特有的遗传变化， 开发定制设计的预处理测试。重要的是，这些数据将成为愿景的基础 个性化医疗，考虑到人口的自然差异，以最大限度地 风险个体的确认和治疗方案的有效性。该项目支持整体 通过促进PSM和MCC调查人员之间的密切合作， 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.