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

• DOI: 10.1158/2767-9764.crc-24-0624
• Publication Date: 2025-03-25T20:03:54Z
• Authors: Roy Elias; Thomas Nirschl; Michael Rezaee; Anirudh Yerrapragada; Shirley Wang; Joseph Cheaib; Ridwan Alam; Sunil Patel; Yuezhou Jing; Mohamad Allaf; David McKean; Alison P. Klein; Elana J. Fertig; Ezra Baraban; Yasser Ged; Srinivasan Yegnas...; Nirmish Singla
• Keywords: Kidney cancer

Abstract Self-reported Black (B) individuals remain underrepresented in molecular studies of clear cell renal carcinoma (ccRCC) relative to White (W) individuals. We performed whole-exome and transcriptome sequencing on paired tumor normal samples from 59 matched B W patients undergoing nephrectomy for localized ccRCC, comparing differences by estimated genetic similarity African (AFR) European (EUR) 1000 Genomes groups. validated our findings with a propensity-matched subset TCGA, yielding final cohort 254 (79 AFR, 175 EUR) similar baseline clinical variables. Significant emerged VHL mutation frequency (AFR: 23.4%, EUR: 57.5%; FDR = 0.0029) chromosome 3p deletions 59.2%, 82.6%; 0.086). Transcriptomic analyses identified 34 genes associated similarity, gene set enrichment revealed inflammatory (interferon gamma/alpha, allograft rejection), proliferative (E2F targets, G2M checkpoint), metabolic (bile acid, fatty glycolysis, MTORC1, peroxisome) pathway EUR. also observed ccRCC subtype distribution, “Proliferative” “Angio/Stromal” subtypes more common AFR (p 0.018). Importantly, differential membership explained most group-level differences. These results link EUR distinct subtypes, underscoring the importance classifiers disease stratification need include diverse populations improve understanding treatment ccRCC.