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: 10335127
• 负责人: JOHN D. CARPTEN
• 金额: $ 127.15万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335127
• 关键词: 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; Environmental Risk Factor; Epidemiology; Estrogen Receptor Status; Etiology; Europe; European; Factor Analysis; Frequencies; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genomics; Genotype; 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; Plant Roots; Population; Preventive; Public Health; Publishing; Reporting; Research; Resources; Risk Factors; Somatic Mutation; Testing; The Cancer Genome Atlas; United States; Ursidae Family; Variant; 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.

项目概要/摘要。非洲裔妇女（AA）和 在美国，欧洲血统（EA）仍然是一个巨大的公共卫生挑战。AA妇女是由高折磨 三阴性乳腺癌（TNBC）的发病率，并承担从所有人口的死亡率最高， 疾病即使在TNBC内部，一些数据也表明AA女性的表现比EA女性更差。越来越多的证据 指出了癌症生物学中可能存在的人群差异，这是一个尚未解决的基本问题。的 差异还表现在肿瘤基因组测序项目的代表性上。的现有数据 乳腺肿瘤突变主要来自EA人群，这可能不代表AA癌症 基因组此外，随着新驱动基因的发现潜力接近平台期，癌症基因组 在不同的遗传和环境背景下提出的AA可能提供了一个强大的场所， 在EA病例中罕见的突变。这在最近的其他癌症类型的研究中得到了明确的证明。因此，在本发明中， 我们在这里提出了一项研究，以表征AA乳腺癌基因组的突变景观， 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性突变标记， 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 肿瘤突变与遗传和环境因素的联系，利用现有丰富的流行病学 和基因型数据资源。我们有四个具体目标。首先，我们将描述 通过对500个肿瘤进行全外显子组测序和RNA测序，在AA女性中进行TNBC。我们将 鉴定并比较AA TNBC病例与EA病例中显著突变的基因和突变特征 从公共数据来源，以测试是否有人口水平的差异。第二，根据数据， 目标1和已发表的文献，我们将组装一个靶向基因面板和序列的额外2,500个氨基酸 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病例的测序项目。目标2中生成的数据将用于确认 目的1，并与来自B-CAST的EA数据相比，进一步评估群体水平的突变差异 以及其他所有癌症亚型的癌症。第三，我们将研究与乳腺癌相关的风险之间的病因学联系， 乳腺癌和体细胞突变的因素。第四，我们将研究遗传祖先和遗传变异 肿瘤突变。在上述数据的基础上，我们将使用 综合分析方法。这项拟议中的工作将大大推进乳腺癌研究领域 通过表征AA人群中的肿瘤突变景观，并确定癌症生物学是否在 体细胞突变水平因祖先群体而异。这些发现可能具有翻译意义， 揭示癌症病因，为癌症预防措施提供新的目标和动力。