Genomic Diversity of Prostate Cancer Across the African Diaspora

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PROJECT SUMMARY/ABSTRACT African descent men (ADM) across the African diaspora have the highest rates of prostate cancer (CaP) of any racial or ethnic group. The incidence rate in African American men (AAM) is 71% higher than in European American men (EAM) and the AAM mortality rate is 210% higher than EAM. Despite the public health implications of these observations, the underlying causes of this disparity remain unresolved. There is substantial evidence that social inequities and access to health care are in part responsible for CaP disparities. There is limited consistent evidence for exposures and environmental factors in CaP etiology or progression. In contrast, CaP is strongly influenced by inherited genetic variation, and there is growing evidence that the mutational landscape of prostate tumors varies substantially by race. These observations suggest that biological factors influence CaP incidence and tumor aggressiveness differentially by race and may in part explain CaP disparities by race. To inform the biological basis of CaP disparities that adversely affect ADM, we have developed a large, multicenter consortium known as “Men of African Descent and Carcinoma of the Prostate” (MADCaP). Using the resources of this consortium, we propose to undertake a study of CaP in ADM to address the following Aims: Aim 1: Identify common genetic variants associated with CaP aggressiveness in ADM; Aim 2: Define histopathological commonalities of prostate tumors in ADM; and Aim 3: Evaluate molecular signatures and subtypes in prostate tumors and determine their relationship to pathological and clinical characteristics in ADM. The proposed research will have innovative impact in a number of ways. We will address the critical need for increased ethnic diversity in cancer genomics data, which to date has been dominated by studies in European ancestral populations. Ethnically diverse genetic data will not only improve our understanding of genomic contributors to cancer etiology and disparities but will also aid in the development and implementation of cancer genomic analysis for all populations, reduce the potential for errors in determining pathogenicity of genetic susceptibility variants, and improve interpretation of cancer risk in all populations including AAM. In undertaking this research, we will enhance infrastructure needed to undertake genomics research in Africa that includes a large, well-annotated sample of systematically collected tumors with clinical and epidemiologic data that can be used to address a variety of research and clinical questions. We have constructed the MADCaP resources to integrate directly with existing publicly available databases, such as TCGA/ICGC and GENIE, to ensure the African data can be readily compared with data from other sources. Our data will also include deep pathology, clinical and risk factor annotation, largely unavailable in current public datasets, to provide a fuller potential to understand underlying disparities in CaP etiology.