Genetic ancestry and stage-specific differences in prostate cancer genomic alterations.

262 Background: Men of African ancestry have higher prostate cancer-specific mortality than men of European ancestry. Socioeconomic and access-to-care factors contribute, but mounting evidence suggests differences in tumor genomics may also play a role. Most prior studies have relied on self-reported race and have evaluated localized and metastatic tumors either in aggregate or in isolation. Whether ancestry-associated genomic differences vary disease stage remains unknown. Methods: We analyzed 3,574 prostate cancer patients with genetically inferred ancestry who underwent matched tumor-normal targeted sequencing via MSK-IMPACT (468 genes). Genetic ancestry was estimated using ADMIXTURE with the 1000 Genomes reference panel; patients were classified as predominantly African (AFR, ≥80% African ancestry; n=291) or European (EUR, ≥80% European ancestry; n=3,283). Somatic mutations, copy-number alterations, gene fusions, and pathogenic germline variants were assessed. Multivariable logistic regression, adjusted for age, Gleason score, and sequencing year, tested for differences by ancestry, stage (localized stage 1-3 vs metastatic stage 4), and ancestry-stage interaction. Results: SPOP mutations demonstrated a significant ancestry-stage interaction (p<0.05), with opposing trends across ancestry groups. In metastatic disease, SPOP alterations were enriched in AFR tumors (OR 1.9; 95% CI, 1.1-3.1) but depleted in EUR tumors (OR 0.7; 95% CI, 0.5-0.9), despite comparable prevalence in localized tumors (AFR 11% vs EUR 10%). ERG fusions were substantially less frequent in AFR tumors overall (localized: 14% vs EUR 50%; metastatic: 24% vs EUR 41%; both p < 0.001). MYC amplification was more common in AFR metastatic tumors (23% vs 15% in EUR; p = 0.01), whereas frequencies in localized disease were similar (13% vs 11%). BRAF mutations were enriched in localized AFR tumors (4% vs 1% in EUR; p = 0.03) but not in metastatic cases. BRCA2 and other DNA repair gene alterations showed no significant differences by ancestry in either stage category. Conclusions: Prostate cancer genomic profiles differ by genetic ancestry, with some differences modulated by disease stage. The novel SPOP ancestry-stage interaction suggests distinct molecular progression pathways in AFR vs EUR men. Many actionable alterations occur at similar rates across ancestries, supporting equitable genomic testing and precision therapy access.