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: 10091976
• 负责人: JOHN D. CARPTEN
• 金额: $ 131.07万
• 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/10091976
• 关键词: Admixture; African; African American; 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.

项目摘要/摘要。非洲血统(AA)和非洲血统(AA)女性之间的乳腺癌健康差异 欧洲血统(EA)在美国仍然是一个巨大的公共卫生挑战。再生障碍性贫血的女性会受到高潮的困扰 三阴性乳腺癌(TNBC)的发生率，并在所有人口中具有最高的死亡率 疾病。即使在TNBC内部，一些数据也表明AA女性的表现比EA女性差。越来越多的证据 指出了癌症生物学中可能存在的群体差异，这是一个仍未解决的根本问题。这个 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 乳腺癌突变以EA人群的病例为主，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生长的氨基酸可能为揭示 EA病例中罕见的突变。这一点在最近对其他癌症类型的研究中得到了明显的体现。因此， 我们在这里提出了一项研究，通过汇集来描述AA乳腺癌基因组的突变图景 资源来自五项研究，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了特有的突变特征， 提供可追踪的癌症病因和异质性的历史记录。因此，我们将对病因进行调查 利用现有丰富的流行病学资料，将肿瘤突变与遗传和环境因素联系起来 和基因分型数据资源。我们有四个具体目标。首先，我们将描述突变的景观 通过对500个肿瘤进行全外显子测序和RNA测序，对再生障碍性贫血妇女的TNBC进行了研究。我们会 鉴定和比较再生障碍性贫血和再生障碍性贫血病例中显著突变的基因和突变特征 来自公共数据来源，以测试是否存在人口水平的差异。第二，基于来自 目标1和发表的文献，我们将组装一个靶向基因小组，并对另外2,500个氨基酸进行测序 肿瘤，包括所有亚型。该设计将涵盖正在进行的乳腺癌B-Cast中包含的所有基因 欧洲EA病例测序项目。在AIM 2中生成的数据将用于验证在 目标1，并与来自B-CAST的EA数据相比较，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癌症。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，我们将研究遗传祖先和遗传变异 与肿瘤突变有关。根据以上数据，我们将使用以下方法确定乳腺癌的病因亚型 综合分析方法。这项拟议的工作将极大地推动乳腺癌研究领域的发展 通过表征再生障碍性贫血人群中的肿瘤突变情况，并确定癌症生物学在 不同祖先群体的体细胞突变水平不同。这些发现可能具有翻译意义，因为 揭示癌症病因，为癌症预防举措提供新的目标和动机。