Uncovering Breast Cancer Predisposition Factors in Puerto Rico

摘要：DNA修复途径和连接DNA修复与细胞周期调节的信号网络，即DNA损伤反应（DDR），构成了癌症发生的核心机制。DNA修复和DDR基因已被证明是乳腺癌遗传易感性和随后肿瘤进展的关键因素。本提案中描述的研究的总体目标是确定DNA损伤反应基因的生殖系和体细胞遗传变化，这些变化是乳腺癌风险的基础，特别是在波多黎各人口中。总的假设是，波多黎各人乳腺癌易感性的生殖系和肿瘤遗传因素可能在质量上或数量上与白人妇女不同。在具体目标#1中，我们将确定与乳腺癌风险相关的基因中生殖系变化的流行程度。我们将对21个与普通人群乳腺癌易感性相关的候选基因进行全面筛选。这些基因中有几个与细胞对DNA损伤的反应有关。我们将利用捕获技术和大规模并行测序来实现这一目标。我们希望确定之前与乳腺癌易感性有关的基因是否也是波多黎各人口中乳腺癌风险的决定因素。在具体目标#2中，我们建议确定参与DNA修复和DDR的基因中体细胞变化的患病率。这将通过从肿瘤样本中制备文库和全外显子组捕获杂交，然后进行大规模平行测序来完成。对DNA修复和DDR基因的体细胞变化的鉴定有望揭示波多黎各人肿瘤发生中发生突变的关键基因。该项目建议检查生殖系和体细胞的变化，从而提供DNA修复和DDR基因中遗传变异在乳腺癌风险和发展中的作用的综合图像。它针对的是西班牙裔人群，这一群体在基因研究中往往代表性不足。我们的发现可能会揭示这一人群特有的遗传变化，从而允许开发定制设计的易感测试。重要的是，这些数据将为考虑人群自然差异的个性化医疗愿景提供基础，以最大限度地识别风险个体和治疗方案的有效性。该项目通过促进PSM和MCC研究人员之间的密切合作来支持U54的整体应用，同时收集将直接改善波多黎各癌症预防和治疗的知识。

ABSTRACT: 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 underlying 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 underlie the risk of breast cancer, specifically in the population of Puerto Rico. The overall hypothesis is that the germ-line and tumor genetic factors underlying 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 predisposition 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 predisposition 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 identification of individuals at risk and the efficacy of therapeutic regimens. This project supports the overall U54 application by fostering the close collaboration between PSM and MCC investigators while gathering knowledge that will directly improve cancer prevention and treatment in Puerto Rico.