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African Americans (AAs) who have PCa typically have more aggressive disease and make up a disproportionate number of the disease deaths, relative to European Americans (EAs). TMPRSS2 translocations, a common event in EA patients, are exploited in diagnostic and prognostic settings, whereas they are diminished in frequency in AA men. Thus, these patients with TMPRSS2 fusion-negative disease represent an under-investigated patient group. We propose that epigenetic events are a significant and alternative driver of aggressive disease in fusion-negative PCa. To reveal epigenetically governed microRNAs (miRNAs) that are enriched in fusion-negative disease and associated with aggressive in AA PCa, we leveraged both our experimental evidence and publically available data. These analyses identified 18 miRNAs that are differentially altered in fusion-negative disease, associated with DNA CpG methylation, and implicated in aggressive and AA PCas. Understanding the relationships between miRNA expression, upstream epigenetic regulation by DNA methylation, and downstream regulation of mRNA targets in fusion negative disease is imperative to understanding the biological basis of the racial health disparity in PCa.

miRNAs as drivers of TMPRSS2-ERG negative prostate tumors in African American men