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: 8728153
• 负责人: Julie Dutil
• 金额: $ 8.92万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728153
• 关键词: Accounting; Adverse effects; BRCA1 gene; BRCA2 gene; Biochemistry; Breast Epithelial Cells; CHEK2 gene; Cancer Center; Cancer Research Project; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Caucasoid Race; Cell Cycle Regulation; Cells; Collaborations; Communities; Coupled; Custom; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Repair Pathway; Data; Defect; Development; FOLH1 gene; Family; Fostering; Foundations; General Population; Genes; Genetic; Genetic Predisposition to Disease; Germ Lines; Germ-Line Mutation; Goals; High Risk Woman; High-Throughput Nucleotide Sequencing; Hispanics; Human Genetics; Individual; Inherited; Knowledge; Left; Libraries; Link; Malignant Neoplasms; Massive Parallel Sequencing; Mediating; Medical; Medicine; Mentors; Methods; Mutate; Mutation; Pathway interactions; Patients; Physicians; Play; Population; Positioning Attribute; Predisposition; Preparation; Prevalence; Proteins; Puerto Rican; Puerto Rico; Regimen; Research; Research Infrastructure; Research Personnel; Research Project Grants; Risk; Role; Sampling; Signal Transduction; Solid; Somatic Mutation; Surveys; Susceptibility Gene; TP53 gene; Technology; Testing; Therapeutic; Time; Translational Research; Treatment Efficacy; Tumor Suppressor Proteins; Vision; Woman; base; cancer prevention; cancer risk; cancer therapy; career development; chemotherapy; design; exome; experience; genetic variant; high risk; improved; inhibitor/antagonist; interest; investigator training; malignant breast neoplasm; medical schools; multidisciplinary; neoplastic cell; programs; response; screening; symposium; tumor; tumor progression; tumorigenesis

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.

摘要：将DNA修复与细胞周期调节（称为DNA损伤反应（DDR））联系起来的DNA修复途径和信号网络构成了癌症发展的中心机制。 DNA修复和DDR的基因已被证明是乳腺癌遗传易感性和随后的肿瘤进展的关键参与者。该提案中描述的研究的总体目的是确定DNA损伤反应基因的种系和躯体遗传变化，这是乳腺癌风险的基础，特别是在波多黎各人群中。总体假设是，波多黎各乳腺癌敏感性的种系和肿瘤遗传因素可能与白种妇女的质量差异或定量差异。在特定的目标＃1中，我们将确定乳腺癌风险涉及的基因种系变化的普遍性。我们将对一般人群中与乳腺癌易感的21个候选基因进行全面筛查。其中几个基因参与了对DNA损伤的细胞反应。我们将使用捕获技术和大量平行的测序来实现这一目标。我们期望确定以前与乳腺癌易感的基因是否也是波多黎各人口中乳腺癌风险的决定因素。在特定的目标＃2中，我们建议确定与DNA修复和DDR有关的基因的体细胞变化的流行。这将通过图书馆样品制备和完全外部捕获杂交，然后进行大量平行测序来实现。 DNA修复和DDR基因中体细胞变化的鉴定有望揭示波多黎各人种群中肿瘤发生突变的关键基因。该项目建议检查种系和躯体变化，从而提供综合的遗传变异在DNA修复和DDR基因在乳腺癌风险和发育中的作用的图景。它针对的是西班牙裔人群，在遗传研究中通常不足以代表。我们的发现可能会发现该人群特有的遗传变化，这将允许开发自定义设计的倾向检验。重要的是，这些数据将为个性化医学的愿景提供基础，该愿景考虑到人群的自然差异，以最大程度地识别有风险的个体和治疗方案的功效。该项目通过促进PSM和MCC调查人员之间的密切合作，同时收集将直接改善波多黎各的癌症预防和治疗的知识，来支持整体U54的应用。