Clear-Cell Renal Cell Carcinoma Molecular Subtypes Differ by African and European Genetic Similarity.

abstractSelf-reported Black (B) individuals remain underrepresented in molecular studies of clear-cell renal cell carcinoma (ccRCC) relative to White (W) individuals. We performed whole-exome and transcriptome sequencing on paired tumor and normal samples from 59 matched B and W patients undergoing nephrectomy for localized ccRCC, comparing molecular differences by estimated genetic similarity to African (AFR) and European (EUR) 1000 Genomes groups. We validated our findings with a propensity-matched subset of The Cancer Genome Atlas, yielding a final cohort of 254 patients (79 AFR and 175 EUR) with similar baseline clinical variables. Significant differences emerged in VHL mutation frequency (AFR: 23.4%, EUR: 57.5%; FDR = 0.0029) and chromosome 3p deletions (AFR: 59.2%, EUR: 82.6%; FDR = 0.086). Transcriptomic analyses identified 34 genes associated with genetic similarity, and gene set enrichment revealed inflammatory (IFN-γ/IFN-α, allograft rejection), proliferative (E2F targets, G2–M checkpoint), and metabolic (bile acid, fatty acid, glycolysis, MTORC1, peroxisome) pathway enrichment in EUR. We also observed differences in ccRCC molecular subtype distribution, with “Proliferative” and “Angio/Stromal” subtypes being more common in AFR (P = 0.018). Importantly, differential subtype membership explained most group-level differences. These results link EUR and AFR genetic similarity to distinct ccRCC molecular subtypes, underscoring the importance of molecular classifiers in disease stratification and the need to include diverse populations in molecular studies to improve our understanding and treatment of ccRCC. SIGNIFICANCE: Our study shows that AFR genetic similarity correlates with distinct ccRCC molecular subtypes. Further research is needed to disentangle environmental and genetic influences. Identifying these differences underscores the critical importance of including racially and ethnically diverse populations in cancer research to ensure more equitable and sustainable outcomes worldwide for all patients.