Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Stress (RESPOND)

摘要-计划项目概述 非裔美国人（AA）男性的发病率高出60%，更有可能被诊断为侵略性 比白色男人多。AA男性侵袭性疾病负担更大的原因尚不清楚，但 可能包括多种因素，包括社会因素，如终生压力、遗传易感性和 肿瘤相关特征，如微环境中的体细胞改变和局部炎症。的 本计划项目的首要目标是揭示与PCa相关的社会和生物因素 嗜酒者互诫协会成员的攻击性为了实现这一目标，我们将建立一个庞大的、全国性的、以人口为基础的 队列研究，RESPOND，（非洲男性前列腺癌研究： 遗传学、免疫学和社会压力），对10,000名患有PCa事件的AA男性进行研究， NPCR美国癌症登记来自包括美国所有AA PCa病例的38%的州。该队列将提供 全面的信息，多层次的压力，在整个生命过程中，如歧视，早期生活逆境， 和邻里紊乱，包括随时间推移的地理空间邻里数据和感知压力程度; 2)生活方式因素和健康行为; 3）疾病特异性因素，包括PSA筛查史和 治疗选择; 4）研究遗传易感性的生殖系DNA，以及5）肿瘤块样本， 体细胞变异的表征和肿瘤微环境的免疫谱分析。无既往研究 试图在一个大样本中获得这些领域的信息，以了解 每个基因的相对贡献以及分子和非遗传成分之间的关系。为了 为了实现这些目标，我们组建了一个由科学家和临床医生组成的多学科团队， 在PCa研究中的记录。利用RESPOND的资源和研究人员的专业知识，我们 设计了一个由四个项目组成的计划项目，这些项目由四个核心支持， 关于确定与AA中PCa疾病侵袭性相关的社会和生物因素的中心主题 男人这些项目包括：跨生命过程的多层次社会压力源调查 侵袭性PCa（项目1）;全基因组发现侵袭性PCa生殖系易感基因座的努力 PCa和检查生殖系和体细胞变异之间的关系（项目2）; PCa肿瘤中潜在的体细胞改变以及与侵袭性疾病相关的生物学途径 （项目3）;以及，详细评估与PCa相关的肿瘤微环境中的炎症 AA男性的攻击性（项目4）。然而，这四个项目中的每一个都涉及一个不同的研究领域， 当一起研究时，创造科学的协同作用和更全面的主要因素， 会导致嗜酒者的前列腺癌。我们将发现的信息很可能会立即产生临床效果。 在改善患者分层和个性化医疗领域的影响。因此，本研究 广泛的深远意义，并解决了众多的挑战，在临床管理的前列腺癌的AA男子。

Abstract – Program Project Overview African American (AA) men have a >60% higher incidence and are more likely to be diagnosed with aggressive PCa than white men. Reasons for the greater burden of aggressive disease in AA men are unknown, but are likely to include a multitude of factors including social factors such as lifetime stress, inherited susceptibility, and tumor-related features such as somatic alterations and local inflammation in the microenvironment. The overarching goal of this Program Project is to uncover the social and biological factors that are related to PCa aggressiveness in AA men. To accomplish this objective, we will establish a large, national, population-based cohort study, RESPOND, (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Social Stress) of 10,000 AA men with incident PCa identified through nine SEER and NPCR U.S. cancer registries from states that include 38% of all AA PCa cases in the U.S.. The cohort will provide comprehensive information on multilevel stressors over the lifecourse such as discrimination, early-life adversity, and neighborhood disorder, including geospatial neighborhood data over time and degree of perceived stress; 2) lifestyle factors and health behaviors; 3) disease-specific factors including PSA screening history and treatment choice; 4) germline DNA to study genetic susceptibility, and 5) tumor block samples for characterization of somatic variation and immune profiling of the tumor microenvironment. No previous study has attempted to obtain information across these domains in a single large sample in order to understand the relative contribution of each and relationships between molecular and non-genetic components. In order to address these goals, we have assembled a multi-disciplinary team of scientists and clinicians with established track records in PCa research. Leveraging the RESPOND resource and investigator expertise, we have designed a Program Project composed of four Projects that are supported by four Cores which are all focused on the central theme of identifying social and biological factors related to PCa disease aggressiveness in AA men. These Projects include: the investigation of multilevel social stressors across the lifecourse in relationship with aggressive PCa (Project 1); genome-wide discovery efforts of germline susceptibility loci for aggressive PCa and examination of the relationship between germline and somatic variation (Project 2); the identification of underlying somatic alterations in PCa tumors and biological pathways that are related to aggressive disease (Project 3); and, a detailed assessment of inflammation in the tumor microenvironment as it relates to PCa aggressiveness in AA men (Project 4). Each of the four Projects address a distinct research domain, however, when studied together, create scientific synergy and a far more comprehensive picture of the major factors that contribute to aggressive PCa in AA men. The information we will discover is likely to have immediate clinical implications in the areas of improved patient stratification and personalized medicine. Hence, this study has broad reaching significance and addresses numerous challenges in the clinical management of PCa in AA men.