Personalized genomic landscape of prostate cancer in African American men reveals novel drivers and therapeutic opportunities.

African American (AA) men experience disproportionately high prostate cancer incidence and mortality. Despite this disparity, current genomic repositories are predominantly derived from European populations, and studies using archived tissues are often limited by stromal contamination. We sought to characterize the high-resolution somatic mutational landscape of AA prostate cancer using a high-fidelity, patient-matched model system to identify population-specific drivers and therapeutic targets. We performed whole-genome sequencing (WGS) on 10 matched pairs of primary cell cultures derived from prostate tumors and adjacent non-malignant tissues of AA patients. Our analyses revealed a complex, heterogeneous landscape characterized by significant genomic instability, including frequent chromothripsis and kataegis signatures. Mutation hotspots were concentrated on chromosomes 1, 2, 3, and X, with the highest mutation density on chromosome 17. Functionally impactful mutations were identified in critical oncogenic pathways, including chromatin remodeling (CHD1, ARID1A, ATRX, KDM6A) and DNA damage response (ATM, BRCA1/2, RAD51). Additionally, we identified potentially novel candidate mutations unique to this AA cohort, distinct from those in European-centric datasets. This study provides a foundational, patient-specific WGS dataset derived from African American prostate cancer cell models. The identification of high-frequency actionable alterations in epigenetic and DNA repair pathways highlights the utility of this renewable resource for developing tailored therapeutic interventions and addressing racial disparities in prostate cancer outcomes.