270 Background: Whole genome sequencing (WGS) of prostate cancers (PC) from American men of African ancestry (AA) is limited despite AA men having twice the incidence of and mortality from PC as compared to their European ancestry (EA) men. Herein we describe analysis of AA PC WGS to identify genomic contributions to incidence and outcome disparities. Methods: WGS data from AA localized hormone naïve (HN) PCs (n = 23) from our institution were combined with publicly available WGS HNPC datasets (n = 5); quantitative predominant genome-wide ancestry was approximated via RFMix. A comparable EA cohort (n = 224) was similarly assembled. Ancestry groups were compared via regression models correcting for Gleason grade, PSA, and pathologic stage. Results: Analysis of known HNPC driver genes revealed lower frequency of PTEN (2/28 v 70/224, 7% v 31%, p = 0.006) and higher frequency of MYC (5/28 v 13/224, 18% v 5%, p = 0.014) and FOXA1 (7/28 v 24/224, 25% v 11%, p = 0.018) alterations in AA tumors relative to EA. An unbiased search for coding and noncoding drivers uncovered recurrent FOXA1 promoter (n = 8, p = 1.1e^-8, RR = 3.92) and gene body protein-coding (n = 5, p = 1.2e^-6, RR = 7.83) mutations, as targets of somatic selection and affecting nearly half of AA cases. Despite comparable tumor mutational burdens in each group, analysis of genome-wide mutational signatures revealed an AA-specific enrichment of SNVs in trinucleotide contexts associated with mismatch repair deficiency (SBS6, p = 1.68e^-2, RR = 49.1). AA tumors also had significantly more small deletions (sig. ID2) relative to EA samples (p = 2.25e^-31, RR = 9.47), implying replication slippage at lagging strands. Finally, AA PC genomes had consistently higher MSI scores relative to EA (median [IQR]: 4.03 [3.8-4.53] v 1.52 [1.21-1.85], p = 2.95e^-44), yet lower than MSI-H colon cancers. These associations were independent of tissue preservation method or source, suggesting they reflect an ancestry-specific mutational process. Comparison of germline and somatic variants between AA and EA uncovered candidate DNA damage response genes (DDR) for further functional validation. Conclusions: Analysis of the largest AA cohort to date of WGS HNPC has revealed an ancestry-specific somatic mutational processes resulting in elevated rate of MMR-linked SNVs, replication-slippage associated small deletions, and MSI, relative to EA. The uniformity of these data suggest that AAs may harbor an inherited factor contributing to increased somatic genomic instability in the HNPC context. These results are compatible with published analyses demonstrating lower expression of DDR genes in AA versus EA PCs. Greater MSI and indels (via neoantigen formation) may explain the higher response proportions in AA PC patients treated with immune- and radiotherapies. Studies are ongoing to define mechanisms via associations between germline predisposition, somatic modification, and transcriptional outcome.