Abstract 5065: Ancestry-related differences in genomic mutations between African American and European American prostate cancer patients

Abstract Background. Somatic mutations accumulate with age in prostate cancer (PCa) tumorigenesis, affecting key driver genes including FOXA1 and SPOP. Significant ancestry-related differences exist in PCa's mutational landscape: CDK12 mutations occur twice as frequently in African Americans (AA) versus European Americans (EA), while TMPRSS2-ERG fusion is more common in EA (∼50%) than AA (∼25%). Despite these differences, comprehensive genome-wide mutational comparisons remain limited. This study elucidates genome-wide mutational differences between ancestries to identify ancestry-specific molecular signatures for improved risk stratification and personalized treatment. Methods. We analyzed whole-genome DNA sequencing from 19 patients across three cohorts: Africans (AF, n=5) from the European Nucleotide Archive (PRJNA412953), AA (n=11), and EA (n=3) from TCGA. Sequencing files aligned to hg38 were processed using R codes and Strand NGS software for recalibration, realignment, and SNP detection. After removing statistical outliers, we compared mutational burden categories including substitutions, insertions, deletions, complex mutations, zygosity patterns, transition/transversion mutations, Ti/Tv ratios, and dbSNP variants. Statistical analysis employed Mann-Whitney U test for groups ≥5 samples or 10,000-iteration permutation test for smaller groups. Results. Whole-genome SNP analysis revealed distinct patterns across AF, AA, and EA. AA versus EA showed significant differences (p<0.05) in most categories: all basic variant types (substitutions: p=0.0149; insertions: p=0.0181; deletions: p=0.0181), zygosity patterns (homozygous: p=0.0174; heterozygous: p=0.0236), transition/transversion mutations (both p=0.0149), Ti/Tv ratios (p=0.0174), and known dbSNP variants (p=0.0149). Complex variants (p=0.1708) and novel variants (p=0.2766) showed no significant differences. AF versus AA revealed significant differences (p<0.05) in nearly all categories: substitutions (p=0.0176), insertions (p=0.005), deletions (p=0.0169), complex variants (p=0.0169), heterozygous variants (p=0.0211), transitions (p=0.0176), transversions (p=0.0052), Ti/Tv ratios (p=0.0047), and both known (p=0.0046) and novel (p=0.0186) variants, except homozygous variants (p=0.7155). These findings indicate AA have developed distinct genetic profiles compared to continental AF, likely from admixture and environmental factors. Conclusion. This genome-wide analysis demonstrates significant ancestry-specific mutational differences in PCa, with AA exhibiting distinct profiles from both AF and EA due to admixture and environmental factors. These findings underscore the need for diverse genomic databases, personalized precision oncology, and validation in larger cohorts. Citation Format: Nicholas S. Korvink, Arash Rezazadeh, Omid Yazdanpanah, Michael McClelland, Farahnaz Rahmatpanah, . Ancestry-related differences in genomic mutations between African American and European American prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5065.