Genomic Diversity of Prostate Cancer Across the African Diaspora

非洲侨民前列腺癌的基因组多样性

• 批准号: 10364057
• 负责人: TIMOTHY R REBBECK
• 金额: $ 132.45万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-07 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364057
• 关键词: Address; Affect; Africa; Africa South of the Sahara; African; African American; African ancestry; Age; American; Biological; Biological Factors; Cancer Etiology; Caribbean region; Characteristics; Clinical; Clinical Data; Critical Care; Data; Data Set; Development; Diagnosis; Disease; Disease Management; Early Diagnosis; Ensure; Environmental Risk Factor; Epidemiology; Ethnic group; Etiology; European; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Germ-Line Mutation; Health Services Accessibility; Histopathology; Incidence; Infrastructure; Inherited; International Agency for Research on Cancer; Knowledge; Lead; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Minority Groups; Modeling; Molecular; Molecular Profiling; Mutation; Obesity; Pathogenicity; Pathologic; Pathology; Population; Prevalence; Prostate; Prostate carcinoma; Prostatic Neoplasms; Public Health; Race; Research; Resources; Risk; Risk Factors; Risk Management; Sampling; Source; Susceptibility Gene; The Cancer Genome Atlas; cancer genetics; cancer genomics; cancer health disparity; cancer risk; cancer therapy; clinical risk; epidemiologic data; ethnic diversity; experience; genetic risk assessment; genetic variant; genomic data; health care availability; health disparity; improved; individualized prevention; innovation; men; modifiable risk; molecular subtypes; mortality; polygenic risk score; predictive modeling; public database; racial disparity; racial diversity; social; social health determinants; transcriptome; transcriptomics; treatment strategy; tumor

PROJECT SUMMARY/ABSTRACT African descent men (ADM) across the African diaspora have the highest rates of prostate cancer (CaP) of any racial or ethnic group. The incidence rate in African American men (AAM) is 71% higher than in European American men (EAM) and the AAM mortality rate is 210% higher than EAM. Despite the public health implications of these observations, the underlying causes of this disparity remain unresolved. There is substantial evidence that social inequities and access to health care are in part responsible for CaP disparities. There is limited consistent evidence for exposures and environmental factors in CaP etiology or progression. In contrast, CaP is strongly influenced by inherited genetic variation, and there is growing evidence that the mutational landscape of prostate tumors varies substantially by race. These observations suggest that biological factors influence CaP incidence and tumor aggressiveness differentially by race and may in part explain CaP disparities by race. To inform the biological basis of CaP disparities that adversely affect ADM, we have developed a large, multicenter consortium known as “Men of African Descent and Carcinoma of the Prostate” (MADCaP). Using the resources of this consortium, we propose to undertake a study of CaP in ADM to address the following Aims: Aim 1: Identify common genetic variants associated with CaP aggressiveness in ADM; Aim 2: Define histopathological commonalities of prostate tumors in ADM; and Aim 3: Evaluate molecular signatures and subtypes in prostate tumors and determine their relationship to pathological and clinical characteristics in ADM. The proposed research will have innovative impact in a number of ways. We will address the critical need for increased ethnic diversity in cancer genomics data, which to date has been dominated by studies in European ancestral populations. Ethnically diverse genetic data will not only improve our understanding of genomic contributors to cancer etiology and disparities but will also aid in the development and implementation of cancer genomic analysis for all populations, reduce the potential for errors in determining pathogenicity of genetic susceptibility variants, and improve interpretation of cancer risk in all populations including AAM. In undertaking this research, we will enhance infrastructure needed to undertake genomics research in Africa that includes a large, well-annotated sample of systematically collected tumors with clinical and epidemiologic data that can be used to address a variety of research and clinical questions. We have constructed the MADCaP resources to integrate directly with existing publicly available databases, such as TCGA/ICGC and GENIE, to ensure the African data can be readily compared with data from other sources. Our data will also include deep pathology, clinical and risk factor annotation, largely unavailable in current public datasets, to provide a fuller potential to understand underlying disparities in CaP etiology.

项目概要/摘要 非洲裔男性 (ADM) 的前列腺癌 (CaP) 发病率最高 任何种族或族裔群体中非裔美国男性 (AAM) 的发病率比欧洲男性高 71%。 美国男性 (EAM) 和 AAM 死亡率比 EAM 高 210%，尽管对公共卫生有影响。 就这些观察结果而言，造成这种差异的根本原因仍未得到解决。 有大量证据表明，社会不平等和获得医疗保健的机会是造成 CaP 的部分原因 CaP 病因学或环境因素的证据有限。 相比之下，CaP 受到遗传变异的强烈影响，并且越来越多的证据表明 前列腺肿瘤的突变情况因种族而异。这些观察结果表明 生物因素对 Cap 发生率和肿瘤侵袭性的影响因种族而异，并且可能部分影响 解释按种族划分的 Cap 差异。 为了了解对 ADM 产生不利影响的 CaP 差异的生物学基础，我们开发了一个大型的、 被称为“非洲人后裔与前列腺癌”(MADCaP) 的多中心联盟。 利用该联盟的资源，我们建议对 ADM 中的 CaP 进行研究，以实现以下目标： 目标 1：识别与 ADM 中 CaP 攻击性相关的常见遗传变异；目标 2：定义 ADM 中前列腺肿瘤的组织病理学共性；以及目标 3：评估分子特征和 前列腺肿瘤的亚型并确定它们与 ADM 病理和临床特征的关系。 拟议的研究将以多种方式产生创新影响，我们将满足这一关键需求。 增加癌症基因组学数据的种族多样性，迄今为止，该数据一直由欧洲的研究主导 祖先群体的种族多样性遗传数据不仅会提高我们对基因组的理解。 造成癌症病因和差异的因素，但也有助于癌症的发展和实施 对所有人群进行基因组分析，减少确定遗传致病性时出现错误的可能性 易感性变异，并改善对包括 AAM 在内的所有人群癌症风险的解释。 这项研究，我们将加强在非洲进行基因组学研究所需的基础设施，其中包括 系统收集的肿瘤的大量、注释清楚的样本，具有临床和流行病学数据，可以 我们构建了 MADCaP 资源来解决各种研究和临床问题。 直接与现有的公开可用数据库（例如 TCGA/ICGC 和 GENIE）集成，以确保 非洲数据可以很容易地与其他来源的数据进行比较，我们的数据还将包括深层病理学、 临床和风险因素注释，在当前公共数据集中基本上不可用，以提供更充分的潜力 了解 Cap 病因学的根本差异。