Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women

非裔美国女性乳腺癌的体细胞突变及其病因决定因素

• 批准号: 10558682
• 负责人: JOHN D. CARPTEN
• 金额: $ 129.16万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558682
• 关键词: Acceleration; Admixture; African American; African American population; African ancestry; Aging; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer gene; Breast Feeding; Cancer Biology; Cancer Etiology; Characteristics; Colon Carcinoma; Companions; DNA Damage; DNA Sequence Alteration; Data; Data Set; Data Sources; Disease; Disparity; Environmental Risk Factor; Epidemiology; Estrogen Receptor Status; Etiology; Europe; European ancestry; Frequencies; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genomics; Genotype; Germ-Line Mutation; Heterogeneity; Hormonal; Hormones; Inflammation; Investigation; Knowledge; Link; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mammary Gland Parenchyma; Mammary Neoplasms; Motivation; Mutate; Mutation; Obesity; Oxidative Stress; Parents; Pathway interactions; Patients; Population; Preventive; Public Health; Publishing; Reporting; Research; Resources; Risk Factors; Somatic Mutation; Testing; The Cancer Genome Atlas; United States; Woman; Work; aggressive breast cancer; anticancer research; base; breast cancer genomics; cancer genome; cancer health disparity; cancer heterogeneity; cancer subtypes; cancer therapy; cancer type; clinically significant; data resource; design; driver mutation; epidemiologic data; exome sequencing; gene panel; genetic variant; genome-wide; immunohistochemical markers; improved; knowledge base; malignant breast neoplasm; mortality; parity; reproductive senescence; targeted sequencing; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumorigenesis

Project Summary/ Abstract. The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a huge public health challenge in the US. AA women are afflicted by a high rate of the triple-negative breast cancer (TNBC), and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest AA women fare worse than EA women. Mounting evidence points to possible population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor genomic sequencing projects. The existing data of breast tumor mutations are dominated by cases from EA populations, which may not represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer genomes in AAs raised in distinct genetic and environmental context may provide a powerful venue for uncovering mutations that are rare in EA cases. This is clearly showcased in recent studies in other cancer types. Thus, we propose here a study to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five studies, which will create the largest AA tumor mutation dataset. We hypothesize that endogenous and exogenous exposures leave characteristic mutational signatures on cancer genome, providing a trackable historic record of cancer etiology and heterogeneity. Thus, we will investigate etiological links of tumor mutations with genetic and environmental factors by leveraging the available rich epidemiologic and genotype data resources. We have four Specific Aims. First, we will characterize mutational landscape of TNBC in AA women by performing whole-exome sequencing and RNA-sequencing of 500 tumors. We will identify and compare significantly mutated genes and mutational signatures in AA TNBC cases with EA cases from public data sources, to test whether there are population-level differences. Second, based on data from Aim 1 and published literature, we will assemble a targeted gene panel and sequence an additional 2,500 AA tumors, inclusive of all subtypes. The design will cover all genes included in B-CAST, an ongoing breast tumor sequencing project of EA cases in Europe. Data generated in Aim 2 will be used to validate SMGs identified in Aim 1, and to further assess population-level mutational differences in comparison to EA data from B-CAST and others across all cancer subtypes. Third, we will examine etiological links between hormone-related risk factors for breast cancer and somatic mutations. Fourth, we will examine genetic ancestry and genetic variants with tumor mutations. On the basis of the data above, we will identify breast cancer etiological subtypes using an integrative analytical approach. The proposed work will greatly advance the field of breast cancer research by characterizing tumor mutational landscape in AA populations and determining whether cancer biology at the somatic mutation level differs by ancestral population. The findings may have translational significance by revealing cancer causation and providing new targets and motivations for cancer preventive initiatives.

项目摘要/摘要。非洲血统 (AA) 和非洲血统女性之间的乳腺癌健康差异 欧洲血统（EA）仍然是美国巨大的公共卫生挑战。 AA 女性饱受高度困扰 三阴性乳腺癌（TNBC）的发病率最高，是所有人群中死亡率最高的 疾病。即使在 TNBC 内部，一些数据也表明 AA 女性的表现比 EA 女性要差。越来越多的证据 指出癌症生物学方面可能存在的人群差异，这是一个尚未解决的基本问题。这 差异还体现在肿瘤基因组测序项目的代表性上。现有数据为 乳腺肿瘤突变以 EA 人群病例为主，这可能并不代表 AA 癌 基因组。此外，随着新驱动基因的发现潜力已接近平台期，癌症基因组 在不同的遗传和环境背景下培养的 AA 可能为揭示 EA 病例中罕见的突变。最近对其他癌症类型的研究清楚地表明了这一点。因此， 我们在此提出一项研究，通过汇集 AA 乳腺癌基因组的突变情况来表征 来自五项研究的资源，这将创建最大的 AA 肿瘤突变数据集。我们假设 内源性和外源性暴露在癌症基因组上留下特征突变特征， 提供癌症病因学和异质性的可追踪历史记录。因此，我们将调查病因 通过利用现有丰富的流行病学知识，研究肿瘤突变与遗传和环境因素的联系 和基因型数据资源。我们有四个具体目标。首先，我们将描述突变景观 通过对 500 个肿瘤进行全外显子组测序和 RNA 测序，对 AA 女性进行 TNBC。我们将 识别并比较 AA TNBC 病例与 EA 病例中的显着突变基因和突变特征 从公共数据来源，检验是否存在人群水平差异。其次，根据数据 目标 1 和已发表的文献，我们将组装目标基因组并对另外 2,500 个 AA 进行测序 肿瘤，包括所有亚型。该设计将涵盖 B-CAST（一种正在进行的乳腺肿瘤）中包含的所有基因 欧洲 EA 案例排序项目。目标 2 中生成的数据将用于验证中识别的 SMG 目标 1，与 B-CAST 的 EA 数据相比，进一步评估群体水平的突变差异 以及所有癌症亚型的其他疾病。第三，我们将检查激素相关风险之间的病因学联系 乳腺癌和体细胞突变的因素。第四，我们将检查遗传血统和遗传变异 与肿瘤突变。根据上述数据，我们将使用以下方法识别乳腺癌病因亚型： 综合分析方法。拟议的工作将极大地推进乳腺癌研究领域 通过表征 AA 人群中的肿瘤突变情况并确定癌症生物学是否 体细胞突变水平因祖先群体而异。研究结果可能具有转化意义 揭示癌症的因果关系，并为癌症预防举措提供新的目标和动机。