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.

项目摘要/摘要。非洲血统妇女（AA）和 在美国，欧洲血统（EA）仍然是一项巨大的公共卫生挑战。 aa妇女受到高高困扰 三阴性乳腺癌（TNBC）的速率，并且在所有人群中的死亡率最高 疾病。即使在TNBC中，一些数据也表明，AA女性的表现要比EA女性差。越来越多的证据 指出了癌症生物学的可能人群差异，这是一个尚未解决的基本问题。这 差异在肿瘤基因组测序项目中的代表性也表现出来。现有数据的 乳腺肿瘤突变由EA种群的病例主导，这可能不代表AA癌 基因组。此外，随着新驱动基因的发现潜力已接近高原，癌症基因组 在不同的遗传和环境环境中提出的AA中，可能为发现的强大场所提供了一个强大的场所 在EA情况下很少发生突变。在其他癌症类型的最新研究中清楚地表明了这一点。因此， 我们在这里提出了一项研究，以通过合并来表征AA乳腺癌基因组的突变景观 五项研究的资源将创建最大的AA肿瘤突变数据集。我们假设这一点 内源性和外源性暴露在癌症基因组上留下特征性突变特征， 提供可追踪的癌症病因和异质性的历史记录。因此，我们将研究病因 肿瘤突变与遗传和环境因素的联系通过利用可用的丰富流行病学 和基因型数据资源。我们有四个具体的目标。首先，我们将表征 AA女性中的TNBC通过对500个肿瘤进行全异位测序和RNA测序。我们将 在AA TNBC病例中识别和比较具有EA病例的AA TNBC病例中显着突变的基因和突变特征 从公共数据源到测试人口级差异。其次，基于来自 AIM 1和已发表的文献，我们将组装一个靶向基因面板，然后再序列2500 AA 肿瘤，包括所有亚型。该设计将涵盖B-Cast中包括的所有基因，这是一种正在进行的乳腺肿瘤 EA案件在欧洲的测序项目。 AIM 2中生成的数据将用于验证在 AIM 1，并进一步评估B-Cast相比的EA数据的人口级突变差异 以及所有癌症亚型的其他人。第三，我们将检查与激素相关风险之间的病因联系 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 肿瘤突变。根据上述数据，我们将使用使用 一种综合分析方法。拟议的工作将大大推动乳腺癌研究领域 通过表征AA种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种群而异。调查结果可能具有翻译意义 揭示癌症因果关系，并为癌症预防措施提供新的目标和动机。