Racial Differences in Prostate Cancer Molecular Subtyping

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ABSTRACT Black men have one of the highest risks of aggressive prostate cancer (PC) in the world. Even in an equal access setting, we found disparities persist, arguing for a biological basis for these disparities. Indeed, Black PCs are less likely than White PCs to have gene fusions such as TMPRSS2-ERG. However, a detailed genomic or epigenomic profiling of Black and White PCs accounting for these differences has never been performed. In a preliminary, but large-scale gene expression analysis of PCs in Black (n=305) and White (n=238) men undergoing surgery, we found multiple differentially activated pathways by race. When stratified by a molecular subtype developed by our team, many differences were only seen in certain subtypes and not others, arguing that any analysis of gene expression differences by race must account for differences in molecular subtyping. Based upon these data, we received an R01 grant (MPI Freeman/Freedland) to perform further analysis of the transcriptomic data along with characterization of a novel master regulator (MR) transcription factor we identified as being important in PC and particularly relevant for Black PCs, ONECUT2. During the work for this R01, we found that when tumors were selected based upon high expression of a pathway that was more active in Black PCs, this enriched for Black men. As such, this is a novel pipeline to enrich for tumor biologies that are most relevant for Black men. Given that many of the top active pathways in Black men were inflammatory related, we propose to study “inflamed” tumors (tumors with high activation of inflammatory pathways) We hypothesize a distinct set of MRs are active in PCs from Black vs. White men and that these MRs drive a differential array of signaling pathways and cellular processes. Characterizing these MRs and understanding their impact on PC gene expression are crucial to identify novel targets enriched in Black or White men. In this one-year diversity supplement to Dr. Tamukong, we propose one specific Aim: Identify race-associated gene expression signatures specific to “inflamed” tumors (i.e. tumors with high activation of inflammatory pathways) and determine their upstream master regulator drivers. To accomplish, we will use the Durham VA transcriptomic data and conducted a detailed bioinformatic analysis to define which tumors are “inflamed”. Within these tumors, we will: 1. Identify differentially expressed genes by race; 2. Determine the top differentially regulated pathways by race; 3. Identify key MRs by race. Despite the fact that work from us and others found Black PCs are more likely to over-express inflammatory pathways, no study has analyzed the differential gene expression patterns specifically within these “inflamed” tumors nor determined the MRs that drive the transcriptional network within these tumors. Our paper in Nature Medicine used the identical pipeline as in this study, which identified a novel MR and potential PC target (ONECUT2). We expect this study will identify broad gene expression programs governed by MRs enriched in Black men within “inflamed” tumors that when targeted, will lead to reduced PC health disparities.