SPECIFIC AIMS
African American men (AAM) suffer from the highest rates of carcinoma of the prostate (CaP) in the world, with an age-adjusted incidence rate of 175.2 per 100,000(1). This rate is 71% higher than that in European American men (EAM; age-adjusted incidence of 102.3 per 100,000). AAM experience a mortality rate 210% higher than EAM (38.1 per 100,000 in AAM vs. 18.1 per 100,000 in EAM)(1). These substantial disparities persist despite a
recent decrease in US CaP incidence and mortality rates. Less is known about the epidemiology of CaP among men in sub-Saharan Africa (SSA). Hsing et al.(2) estimated that the rate of CaP in Africa may be as high or higher than that in AAM. IARC estimates that CaP is the leading cancer in terms of both incidence and mortality in men in SSA and the Caribbean(3). IARC also estimates that the number of CaP cases in SSA is predicted to more
than double (i.e., an increase of 112%) in the next two decades(3).
Despite the public health implications of this disparity worldwide, the underlying causes of the observed disparity in CaP incidence and mortality in African descent men (ADM), including AAM, remain unresolved. There are few consistent epidemiological risk factors for CaP and only obesity has been confirmed as a potentially modifiable risk factor for aggressive CaP(4). Recent evidence suggests that the disparity in CaP mortality could be reduced or eliminated if access to appropriate cancer treatment were equalized across racial groups(5). Thus, social determinants of health and access to health care are critical in our understanding of CaP disparities in AAM. However, because the incidence of CaP is higher in AAM than EAM, even if treatment and access could be equalized across racial groups, the disparity in CaP at the population level would persist due to the elevated
incidence of disease in AAM.
In contrast to the limited evidence for modifiable risk factors in CaP etiology, there is growing evidence for biological differences in CaP etiology by race. The mutational landscape of prostate tumors varies substantially by race: Tumor location within the prostate and molecular tumor features appear to be systematically different in
AAM compared with men of other races(6, 7). It is not clear whether these features also differ in African men, or whether there are features common in both African men and AAM that are distinct from the features in EAM. If prostate tumor genomic and histopathological features can be identified that are unique to ADM, including AAM, this knowledge may be used to explain the biological basis of CaP disparities.
We hypothesize that the prostate tumors of ADM, including AAM, have histopathological and genomic features that are distinct from those of EAM. The identification of these unique features may (in part) explain biologically driven disparities in CaP aggressiveness by race. A better understanding of genomic and histopathological features unique to ADM may inform biologically-informed (precision) prevention, early detection, and treatment strategies to ameliorate CaP disparities.
We propose to evaluate the relationship of common germline mutations, tumor gene expression, and tumor histopathology that underlie CaP aggressiveness. We will leverage a large, multicenter consortium known as the “Men of African Descent and Carcinoma of the Prostate Network (MADCaP; www.madcapnetwork.org) as well as publicly available data to address the following specific aims:
Specific Aim 1: Identify common genetic variants associated with CaP aggressiveness in ADM.
Hypothesis: Gene expression prediction models, transcriptome-wide associations, trans-ethnic molecular colocalization models, and interactions between germline (e.g., polygenic risk scores) and somatic (e.g., transcriptomic risk scores) can identify common genetic variants that predict CaP aggressiveness that are unique to ADM.
Specific Aim 2: Define histopathological commonalities of prostate tumors in ADM.
Hypothesis: Histopathological features of prostate tumors that are unique to ADM (i.e.,
AAM/African vs. EAM) can be identified that in part explain disparities in CaP aggressiveness.
Specific Aim 3: Evaluate molecular signatures and subtypes in prostate tumors and their relationship to histopathological and clinical characteristics at diagnosis in ADM.
Hypothesis: Molecular profiles specific to ADM (i.e., AAM/African vs. EAM) define tumor
features that contribute to our understanding of prostate cancer disparities.
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