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.

摘要 非裔美国人和非裔美国人乳腺癌（BC）发病率和预后的健康差异 西班牙裔人口至少部分归因于遗传因素， 人口。我们的长期目标是了解种群间和个体间的遗传 变化调节BC风险。在我们以前的工作中，我们已经使用混合映射的人口 波多黎各，以确定基因组易感BC的区域。这导致了对 3个易感基因座（7p15.3、10q21.1和14q24.1），其中2个基因座未见报道。 有趣的是，10q21.1基因座的非洲血统与三重遗传的风险增加有关。 阴性阴性肿瘤，其缺乏雌激素（ER）、孕激素（PR）的表达， 人上皮生长因子（HER 2）受体，并且已知与不良预后相关。 在此更新申请中，我们建议继续开展以下工作。在具体目标#1中，我们将确定 通过密集阵列的关联分析，在混合物信号中常见和罕见的遗传变异 单核苷酸多态性（SNP）和靶向测序。在具体目标#2中，我们建议 通过以下方式鉴定参与决定乳腺肿瘤体细胞特征的基因组区域： 对按表达亚型和常见突变分层的乳腺肿瘤进行混合作图 status.在具体目标#3中，我们将进一步探讨在乳腺癌易感性中涉及的遗传因素， 通过对已知的全基因组关联研究（GWAS）基因座进行复制研究，在波多黎各进行。 本申请提出了一个综合和创新的战略，以提高我们的作用的理解 它针对的是西班牙裔人口，他们在遗传和 基因组学研究。随着共同的遗传变异的发现，可以累积识别 风险分布的极端，人们可以开始设想通过以下方法精确预防乳腺癌： 在风险水平与适当的减少风险干预措施之间取得平衡。结果从拟议的 研究可为实现这一目标作出重要贡献。预计拟议项目将产生积极影响 对PI的职业生涯提供高质量的手稿，这将导致准备的基础， R型融资。Dutil博士在分子遗传学和基因组学方面训练有素， 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; 是统计遗传学和混合作图领域的领导者; Fejerman博士是 在拉丁裔人群中使用BC混合物和GWAS。