Molecular profiling of clear cell RCC (ccRCC) tumors of clinical trial patients has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC (n = 508) and centrally-reviewed nccRCC (n = 149) samples. ccRCC had increased angiogenesis signature scores compared to the heterogeneous group of nccRCC tumors (mean z-score 0.37 vs -0.99, P < 0.001), while cell cycle, fatty acid oxidation (FAO)/AMPK signaling, fatty acid synthesis (FAS)/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T-effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMB-High/MSI-High). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC vs nccRCC tumors, providing new insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

Original languageEnglish
JournalJournal of Clinical Investigation
Issue number11
Early online dateMar 23 2024
StatePublished - Mar 23 2024


  • Aged
  • Carcinoma, Renal Cell/genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms/genetics
  • Male
  • Middle Aged
  • Neoplasm Proteins/genetics
  • Transcriptome


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