Circulating cell-free DNA profiling reveals ancestry-dependent genetic variation in metastatic prostate cancer.

African American men experience markedly higher prostate cancer incidence and mortality yet remain underrepresented in genomic studies aimed at identifying ancestry-associated molecular drivers of disease progression. Circulating cell-free DNA (cfDNA) provides a minimally invasive means of capturing tumor-derived genomic alterations and enables broad characterization of molecular heterogeneity. In this study, we performed comprehensive plasma cfDNA profiling in 22 African American and 66 Caucasian men with metastatic castration-resistant prostate cancer (mCRPC) to define ancestry-related differences in mutation landscapes. Across samples, we identified 281 variants within 88 genes, with African American patients exhibiting a significantly higher burden of differentially frequent mutations. Integration of Gene Ontology analysis, KEGG pathway mapping, and functional enrichment revealed ancestry-dependent perturbations in pathways central to prostate cancer biology, including PI3K-AKT, MAPK, androgen signaling, DNA repair, and cell-cycle regulation. A panel of 25 genes emerged as key contributors to divergent disease mechanisms across racial groups. Several variants enriched in African American patients involved genes regulating genomic stability and treatment resistance, offering potential insight into observed clinical outcome disparities. These findings provide a comprehensive, ancestry-informed cfDNA mutational landscape in mCRPC and highlight biologically meaningful differences that may support the development of non-invasive biomarkers, improved risk stratification, and ancestry-tailored precision oncology strategies.