Inherited genetic factors in breast cancer predisposition and tumor presentation

乳腺癌易感性和肿瘤表现的遗传因素

• 批准号: 9977273
• 负责人: Julie Dutil
• 金额: $ 39.2万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977273
• 关键词: 10q21; Admixture; African; African American; Bioinformatics; Biological; Breast Cancer Genetics; Breast Cancer Prevention; Breast Cancer Risk Factor; California; Cancer Prognosis; Characteristics; Chromosome Mapping; Classification; Data; Diagnosis; Disease; Epithelial; Epithelium; Equilibrium; Estrogens; European; Frequencies; Funding; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genome; Genomic Segment; Genomics; Goals; Growth Factor; Growth Factor Receptors; High Prevalence; Hispanic Americans; Hispanics; Human; Incidence; Individual; Infrastructure; Inherited; Intervention; Latina; Lead; Linkage Disequilibrium; Mammary Neoplasms; Manuscripts; Molecular Genetics; Mutation; Native Americans; Outcome; PIK3CA gene; Piedra; Population; Positioning Attribute; Predisposition; Preparation; Prevalence; Progesterone; Puerto Rican; Puerto Rico; Race; Regimen; Reporting; Research Personnel; Risk; Risk Reduction; Role; SNP array; Sampling; San Francisco; Signal Transduction; Somatic Mutation; Statistical Study; Susceptibility Gene; TP53 gene; Time; Training; Translating; Treatment Efficacy; Variant; Vision; Woman; Work; admixture mapping; burden of illness; cancer subtypes; career; disorder risk; experience; falls; genetic association; genetic makeup; genetic risk factor; genetic variant; genome wide association study; genomic data; health disparity; improved; individualized prevention; innovation; malignant breast neoplasm; molecular subtypes; multidisciplinary; mutational status; next generation sequencing; outcome forecast; personalized medicine; precision medicine; rare variant; receptor expression; risk variant; targeted sequencing; tumor

ABSTRACT Health disparities in the incidence and prognosis of breast cancer (BC) in African American and Hispanic populations have been at least partly attributed to genetic factors that distinguish these populations. Our long-term objective is to understand how inter-population and inter-individual genetic variations modulate BC risk. In our previous work, we have used admixture mapping in the population of Puerto Rico to identify regions of the genome predisposing to BC. This has led to the identification of three susceptibility loci (7p15.3, 10q21.1 and 14q24.1), two of which have not been reported before. Interestingly, African ancestry at the 10q21.1 locus was associated with an increase risk of triple negative negative tumors, which lack the expression of the estrogen (ER), progesterone (PR) and human epithelial growth factor (HER2) receptors and is known to be associated with a poor prognosis. In this renewal application, we propose to pursue this work as follow. In Specific Aim #1, we will identify common and rare genetic variants within the admixture signals by association analysis of a dense array of single nucleotide polymorphisms (SNPs) and targeted sequencing. In Specific Aim #2, we propose to identify the genomic regions involved in determining the somatic characteristics of breast tumors by conducting admixture mapping of breast tumors stratified by expression subtype and common mutation status. In Specific Aim #3, we will further explore the genetic factors involved in BC susceptibility in Puerto Rico by performing a replication study of known genome-wide association study (GWAS) loci. This application proposes an integrated and innovative strategy to improve our understanding of the role of genetics in BC and it targets a Hispanic population, which is often underrepresented in genetic and genomics studies. With the discovery of common genetic variants that may cumulatively identify the extremes of the risk distribution, one can begin to envision precision prevention of breast cancer by balancing the level of risk with appropriate risk reduction interventions. The results from the proposed study can contribute importantly to this goal. The proposed project is expected to have a positive impact on the PI's career by providing the basis for the preparation of high quality manuscripts that will lead to R-type funding. Dr. Dutil is well trained in molecular genetics and genomics and is surrounded by a strong multidisciplinary team: Dr. Massey is an expert in bioinformatics applied to genomic data; Dr. Ziv is a leader in the field of statistical genetics and admixture mapping; and Dr. Fejerman is a pioneer in using BC admixture and GWAS in Latina populations.

抽象的 非裔美国人和 西班牙裔人口至少部分归因于区分这些因素 人群。我们的长期目标是了解人口间和个体间的遗传 变化调节BC风险。在我们以前的工作中，我们在人口中使用了混合映射 波多黎各确定偏见于卑诗省的基因组区域。这导致了 三个易感基因座（7p15.3，10q21.1和14q24.1），其中两个以前没有报道过。 有趣的是，非洲血统在10q21.1基因座与增加三倍的风险有关 阴性阴性肿瘤，缺乏雌激素（ER），孕酮（PR）和 人类上皮生长因子（HER2）受体，已知与预后不良有关。 在此续订应用程序中，我们建议从事这项工作如下。在特定的目标＃1中，我们将确定 混合信号内的常见和稀有遗传变异通过密集阵列的关联分析 单核苷酸多态性（SNP）和靶向测序。在特定目标2中，我们建议 确定通过确定乳腺肿瘤的体细胞特征所涉及的基因组区域 通过表达亚型分层的乳腺肿瘤进行混合图和公共突变 地位。在特定的目标＃3中，我们将进一步探讨BC敏感性涉及的遗传因素 波多黎各通过对已知基因组关联研究（GWAS）基因座的复制研究。 该应用程序提出了一种综合而创新的策略，以提高我们对角色的理解 卑诗省的遗传学和它针对的是西班牙裔人口，在遗传和 基因组学研究。随着发现常见的遗传变异，可能会累积地识别 风险分布的极端，可以通过 平衡风险水平与适当的风险降低干预措施。提议的结果 研究可以为这一目标做出重要贡献。拟议的项目有望产生积极的影响 在Pi的职业生涯中，通过为准备高质量手稿的基础提供基础 R型资金。 Dutil博士接受了分子遗传学和基因组学训练有素的训练，并被A所包围 强大的多学科团队：Massey博士是应用于基因组数据的生物信息学专家； Ziv博士 是统计遗传学和混合映射领域的领导者； Fejerman博士是 在拉丁裔种群中使用BC混合和GWA。