Renal cell carcinoma histologic subtypes exhibit distinct transcriptional profiles

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial 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 and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/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^hi/MSI^hi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.