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.
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