Germline and Tumor Genomic Analyses of Breast Cancer in Latinas

拉丁裔乳腺癌的种系和肿瘤基因组分析

• 批准号: 8673705
• 负责人: Susan L. Neuhausen
• 金额: $ 90.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673705
• 关键词: Accounting; African American; Age; Alleles; Asians; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Biological; Cancer Etiology; Cancer-Predisposing Gene; Candidate Disease Gene; Cataloging; Catalogs; Caucasians; Caucasoid Race; Central American; Cessation of life; Clinical; Custom; DNA; DNA Sequence; Data; Data Set; Decision Making; Diagnosis; Disease; Event; Exhibits; Family; Formalin; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic screening method; Genomics; Germ-Line Mutation; Goals; Hereditary Disease; Incidence; Individual; Inherited; Latina; Latino; Malignant Neoplasms; Mammary Neoplasms; Measures; Medicine; Mexican Americans; Minority; Mutation; Oncogenes; Paraffin Embedding; Population; Predisposition; Preventive; RNA; Recording of previous events; Recurrence; Risk; Risk Assessment; Sampling; Somatic Mutation; Staging; Susceptibility Gene; Technology; Testing; The Cancer Genome Atlas; Tissues; United States; Variant; Woman; base; cancer risk; design; exome sequencing; gene discovery; gene panel; genome wide association study; high risk; insight; loss of function mutation; malignant breast neoplasm; nano-string; next generation sequencing; prevent; public health relevance; rare variant; risk variant; tumor

DESCRIPTION (provided by applicant): With advances in technology, genomics is becoming increasingly important for precision medicine, both for determining risk to develop disease and for treatment decisions. The high-risk breast cancer genes, BRCA1 and BRCA2, were discovered in the mid-1990s. Since then, many other risk loci have been identified by genome-wide association and, more recently, by sequencing studies. However, despite these efforts, the combined effects of known breast cancer loci only explain approximately one-third of the genetic risk. Most of the genes predisposing to breast cancer still have not been identified, thus limiting the potential for identification of many individuals at high risk of developing the disease. Whole-exome sequencing is a potentially powerful approach to discover rare mutations in genes that may be associated with breast cancer susceptibility. However, the number of variants discovered in these studies is large and prioritizing them for replication is difficult. Somatic mutations and copy number and other changes in genes in tumors may provide biological insights that can guide gene selection for replication. In particular, many cancer susceptibility genes act by a pathogenic mutation of the germline copy and then somatic inactivation of the second copy. Use of datasets such as The Cancer Genome Atlas (TCGA) may help to identify additional cancer genes by determining which genes display germline and somatic events in the same individual. However, Latinos, African Americans and Asians are under-represented in TCGA, and because rare variants are usually population specific, it is important that populations of all ancestral backgrounds be included in gene discovery. Latinos represent the largest and fastest-growing minority population in the U.S., yet they have been largely under-studied in terms of genetic susceptibility to breast cancer. Although Latinas have an overall lower incidence of breast cancer than non-Latina Caucasians, Latinas are more likely to be diagnosed at a younger age and to have more aggressive disease at diagnosis. Our proposal will use a combined germline and somatic genetics approach to discover breast cancer susceptibility genes in Latinas. In Specific Aim 1, we will identify mutations in genes from whole-exome sequencing of 1,400 Latina breast cancer cases diagnosed under age 50 and/or with a family history and 1,400 healthy Latina controls. We will perform gene-based association tests to prioritize genes based on p-value for more testing in Aim 2 and for replication in Aim 3. In Specific Aim 2, we will perform targeted sequencing and expression analysis of 800 genes from Aim 1 in DNA and RNA from 384 breast tumors of cases from Aim 1. In Specific Aim 3, we will use custom capture to target and sequence the top 1,000 candidate genes in 2,300 Latina breast cancer cases and 2,300 controls. At the end of this project, we will have identified a set of genes that are significantly associated with breast cancer in Latinas. A long-term goal is to develop a clinical genetic test that can help to determine risk in individual Latinas who have not been diagnosed to aid in their decision-making with regard to preventive options.

描述（由申请人提供）：随着技术的进步，基因组学对于精准医学变得越来越重要，无论是对于确定患病风险还是对于治疗决策。高风险乳腺癌基因 BRCA1 和 BRCA2 于 20 世纪 90 年代中期被发现。从那时起，许多其他风险基因座已通过全基因组关联以及最近的测序研究被确定。然而，尽管做出了这些努力，已知乳腺癌基因座的综合影响只能解释大约三分之一的遗传风险。大多数乳腺癌易感基因尚未确定，因此限制了乳腺癌的发生。 识别许多患有该疾病的高风险个体的潜力。全外显子组测序是一种潜在的强大方法，可以发现可能与乳腺癌易感性相关的基因中的罕见突变。然而，这些研究中发现的变异数量很大，很难对它们进行优先复制。肿瘤中基因的体细胞突变和拷贝数以及其他变化可能提供生物学见解，指导复制的基因选择。特别是，许多癌症易感性基因通过种系拷贝的致病性突变然后第二个拷贝的体细胞失活起作用。使用癌症基因组图谱 (TCGA) 等数据集可能有助于通过确定哪些基因在同一个体中显示种系和体细胞事件来识别其他癌症基因。然而，拉丁裔、非裔美国人和亚洲人在 TCGA 中的代表性不足，而且由于罕见变异通常是特定人群，因此将所有祖先背景的人群纳入基因发现中非常重要。拉丁裔是美国规模最大、增长最快的少数族裔群体，但他们对乳腺癌遗传易感性的研究在很大程度上还不够充分。尽管拉丁裔的乳腺癌发病率总体上低于非拉丁裔白种人，但拉丁裔更有可能在较年轻的时候被诊断出来，并且在诊断时患有更具侵袭性的疾病。我们的提案将使用种系和体细胞遗传学相结合的方法来发现拉丁裔的乳腺癌易感基因。在具体目标 1 中，我们将从 1,400 名 50 岁以下和/或有家族史的拉丁裔乳腺癌病例和 1,400 名健康拉丁裔对照者的全外显子组测序中鉴定基因突变。我们将进行基于基因的关联测试，根据 p 值对基因进行优先排序，以便在目标 2 中进行更多测试并在目标 3 中进行复制。在特定目标 2 中，我们将对 DNA 中目标 1 的 800 个基因进行靶向测序和表达分析以及来自目标 1 中 384 个乳腺肿瘤病例的 RNA。在特定目标 3 中，我们将使用定制捕获来定位和测序 2,300 个拉丁裔乳腺癌病例中的前 1,000 个候选基因，以及2,300 个控件。在该项目结束时，我们将鉴定出一组与拉丁裔乳腺癌显着相关的基因。长期目标是开发一种临床基因测试，帮助确定尚未确诊的拉丁裔个体的风险，以帮助他们做出有关预防选择的决策。