African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing ( = 102) and targeted validation ( = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in , an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed deletions in 3% of primary prostate cancers and mutations or deletions in in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications. Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of as a prostate cancer gene; somatic copy-number alteration differences; and uncommon and alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. .