African American (AA) men have a >60% higher incidence, are more likely to be diagnosed with aggressive and potentially lethal PCa, and are more than twice as likely to die from PCa than white (WH) 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. RESPOND (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Immunity and Social Stress) has been funded to study the reasons for increased risk of aggressive disease among AA and will include a comprehensive approach including the role of stress and the contextual environment (Project 1), germline susceptibility (Project 2), tumor somatic genetics (Project 3), inflammatory tumor microenvironment (Project 4), and, the integrated synergistic effects of these factors. Project 1: Social stress: AA men are uniquely exposed to high levels of social adversity such as discrimination, violence, crime, financial strain, and residence in poor-resourced environments, over their lifetime. These social stressors are experienced at multiple levels, including individual, neighborhood, and institutional, ultimately leading to chronic and long-term stress. Social stressors may be a contributor to the development of aggressive PCa and high mortality. Project 2: Germline genetic factors: There is evidence to suggest genetic differences in the allelic architecture of PCa across populations. We found a region of the genome (8q24) that harbored genetic risk alleles that may contribute to the greater risk of PCa in AA men. Substantially larger collections of AA cases are needed to reveal a common susceptibility locus that is specific to high-risk disease. We will be expanding genome-wide efforts to identify susceptibility alleles for aggressive PCa in AA men. Project 3: Somatic genetic factors. PCa is a heterogeneous and multifocal disease with a diverse genetic component. Few genetic or molecular drivers of aggressive disease have been identified, and studies in AA men are critically limited. This is due to the fact that the majority of PCa profiling studies have focused on localized disease and largely on men of European ancestry. We will address this issue through the comprehensive and integrated genomic and transcriptomic analysis of a large number of clinically annotated aggressive vs. nonaggressive PCas in AA men. We anticipate that this study will identify genomic markers of aggressive PCa in general and AA PCa in particular, with some of these somatic events being therapeutically actionable, leading to new treatment paradigms for this lethal disease. Project 4: Inflammatory tumor microenvironment. There is evidence to suggest that inflammation drives the formation of precursor lesions to PCa development and may contribute to PCa progression. The consistent observation of overexpression of genes involved in inflammatory pathways in PCa tumors from AA men points to a proinflammatory immune cell component in the tumors of these men that may contribute to PCa progression and their higher PCa mortality. Integration of social and genetic information: Independently evaluating germline, somatic genome, and tumor microenvironment characteristics of PCa ignores the potential for shared biologic mechanism(s). The integration of data across these domains will lead to the identification of shared genes and/or pathways that define more homogeneous, and clinically important, subsets of PCa tumors. The vast genomic and molecular data generated in the same individuals will facilitate the estimation of tumor subgroups as a function of somatic and tumor microenvironment and an assessment of their relationship with other potential PCa risk factors, such as socioeconomic factors, lifetime stress, and genomic germline variation. We will evaluate the association of integrated molecular profiles with recurrence and survival in the future. The RESPOND Cohort: We are in the process of recruiting a cohort of 10,000 incident AA PCa cases to support the four research projects. The men, diagnosed between 2015-2018, are being recruited through cancer registries in 7 states (California, Florida, Georgia, Louisiana, Michigan, New Jersey, and Texas). The fieldwork procedures include enrolling the men by completion of a mailed (or online) survey, followed by a request to obtain a saliva sample and HIPAA authorization to obtain tumor tissue. Of the ~23,000 AA PCa patients we will contact, we estimate to receive a survey from 45% (10,050), DNA from 33% (7,543), HIPAA release from 26% (6,030) and tumor samples for 13% (3,015). Impact: In Project 1, we are studying the impact of multilevel stressors over the lifecourse on risk of developing aggressive and lethal PCa, providing both a means of identifying high-risk men for targeted prevention and treatment, as well as informing the etiology by which tumor aggressiveness arises. In Project 2, the ability to better understand, based on inherited variation, which AA men are at greater risk of developing aggressive and lethal PCa will help in the development of targeted screening and prevention strategies. In Project 3, delineating the genomic events that are acquired during the development of PCa in AA men may guide the development of targeted therapeutic strategies for men whose tumors display aggressive molecular signatures. In Project 4, the ability to define immune profiles associated with aggressive PCa in AA men could inform the development of cancer prevention and/or treatment strategies. Altogether, this body of research will provide impactful information as to the underlying factors that contribute to aggressive PCa in AA men.

Citation Format: Ann S. Hamilton, Scarlett Gomez, Xiao-Cheng Wu, Kevin Ward, Melissa Bondy, Rosemary Cress, Jennifer Beebe-Dimmer, Karen Pawlish, Jong Park, Iona Cheng, Antoinette Stroup, Thomas Sellers, Susan Gundell, Angelo Demarzo, Denise Modjeski, Stephen Chanock, Salma Shariff-Marco, Mindy DeRouen, John Carpten, Franklin Huang, Karen Sfanos, Tamara Lotan, David Conti, Christopher Haiman. A comprehensive and integrated approach to identify factors associated with aggressive prostate cancer in African-Americans: The RESPOND Study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA22.