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.
The Genetic Basis of Aggressive Prostate Cancer: The Role of Rare Variation (PI Haiman: R01CA196931):
Prostate cancer (PCa) is the most common cancer in men with 220,000 new cases and 27,000 deaths estimated this year in the U.S. The vast majority of these deaths occur among the approximately 10-15% of cases diagnosed with aggressive PCa. There are few known risk factors for PCa beyond age, African descent and a family history of PCa, and there are no risk factors that can determine which men will develop aggressive versus non-aggressive disease. Multiple lines of evidence indicate a substantial heritable component of aggressive PCa. Over the past decade, genome-wide association studies (GWAS) have identified over 100 common susceptibility loci that collectively account for 33% of the familial risk of PCa. These loci contribute equally to risk of aggressive and non-aggressive disease which suggests they play a role in the very early stages of PCa tumor evolution. Recent sequencing studies have revealed rare coding variants (well under 1%) in genes such as BRCA1/2 and other DNA repair pathway genes that convey larger risks (3-5 fold) of aggressive PCa relative to non-aggressive disease. These observations suggest that the allelic architecture of aggressive disease may be quite different than overall PCa, and highlight the need for larger efforts focused on rare genetic variation (<1%). This spectrum of variation represents ~80% of all genetic variation in the human genome and is not adequately surveyed through GWAS. In this study, we will apply a multi-staged approach to reveal genes harboring rare variants that are associated with aggressive PCa. Whole-exome sequencing (Aim 1a) of 2,000 aggressive cases and 2,000 non-aggressive cases of European ancestry will be conducted followed by rare variant analysis of single sites and gene burden testing to identify novel susceptibility loci/genes for aggressive disease. We will validate the most significantly associated genes (~500) through targeted sequencing in an additional 7,500 aggressive and 7,500 non-aggressive cases (Aim 1b). Next, we will investigate the clinical predictive utility of the genes/variants identified in 2,300 cases in the STHM3 trial who are undergoing biopsy based on PSA and genetic risk score stratification (Aim 2). Last, we will examine whether the genes identified in Aim 1 contribute to the greater risk of aggressive PCa in 4,000 men of African ancestry (Aim 3). Through this tiered approach we expect to significantly advance knowledge of aggressive PCa etiology and health disparities as well as guide the development of early detection and prognostic strategies for the subset of men who are most susceptible to this fatal form of disease.