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修复与细胞周期调节联系起来的信号网络，被称为