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 非洲裔美国人(AA)男性的发病率高出60%，更有可能被诊断为攻击性疾病 前列腺癌比白人男性更严重。AA男性侵袭性疾病负担较大的原因尚不清楚，但有以下几点 可能包括多种因素，包括社会因素，如生活压力、遗传易感性和 与肿瘤相关的特征，如微环境中的躯体改变和局部炎症。这个 该计划项目的总体目标是发现与前列腺癌相关的社会和生物因素 AA男性的攻击性。为了实现这一目标，我们将建立一个以国家、人口为基础的大型 队列研究，RESPONSE，(关于非洲血统男性前列腺癌的研究：确定 遗传学、免疫力和社会应激)10,000名AA男性患者通过9个SEER和 NPCR美国癌症登记来自各州，包括美国38%的AA PCA病例。该队列将提供 关于生活过程中的多层次压力源的综合信息，如歧视、早年逆境、 以及邻里混乱，包括随时间推移的地理空间邻里数据和感知到的压力程度； 2)生活方式因素和健康行为；3)疾病特有因素，包括PSA筛查史和 治疗选择；4)胚系DNA研究遗传易感性，以及5)肿瘤块样本 肿瘤微环境的体细胞变异和免疫特性的表征。没有先前的研究 试图在单个大样本中获取这些领域的信息，以了解 每种成分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，我们组建了一支由多学科科学家和临床医生组成的团队 在PCA研究方面的记录。利用应急资源和调查人员的专业知识，我们拥有 设计了一个由四个核心支持的四个项目组成的计划项目，这四个核心都是重点 关于确定与再生障碍性贫血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：对人际关系中生活过程中的多层次社会压力源进行调查 攻击性PCA(项目1)；攻击性生殖系易感基因座的全基因组发现工作 主成分分析和种系与体细胞变异关系的检验(项目2)；鉴定 前列腺癌中潜在的躯体改变和与侵袭性疾病相关的生物学途径 (项目3)；以及对肿瘤微环境炎症的详细评估，因为它与前列腺癌有关 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不同的研究领域， 当一起学习时，创造科学的协同效应，并对主要因素进行更全面的描述 有助于AA男性的进攻性PCA。我们将发现的信息很可能立即具有临床意义 在改善患者分层和个性化医疗方面的影响。因此，这项研究具有 具有广泛的深远意义，并解决了AA男性PCa临床管理中的众多挑战。

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.