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.
The Journal of clinical investigation. 2024 Apr 23 [Epub ahead of print]
Pedro Barata, Shuchi Gulati, Andrew Elliott, Hans J Hammers, Earle F Burgess, Benjamin A Gartrell, Sourat Darabi, Mehmet A Bilen, Arnab Basu, Daniel M Geynisman, Nancy A Dawson, Matthew R Zibelman, Tian Zhang, Shuanzeng Wei, Charles J Ryan, Elisabeth I Heath, Kelsey A Poorman, Chadi Nabhan, Rana R McKay
Department of Internal Medicine, University Hospitals Seidman Cancer Center, Cleveland, United States of America., Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, United States of America., Clinical and Translational Research/Medical Affairs, Caris Life Sciences, Irving, United States of America., UT Southwestern Kidney Cancer Program, UT Southwestern Medical Center, Dallas, United States of America., Department of Internal Medicine, Levine Cancer Institute Atrium Health, Charlotte, United States of America., Department of Medicine, Division of Oncology, Albert Einstein College of Medicine, Bronx, United States of America., Clinical Genomics, Hoag Memorial Hospital Presbyterian, Newport Beach, United States of America., Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America., Department of Medical Oncology, University of Alabama, Birmingham, United States of America., Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, United States of America., Department of Internal Medicine, Georgetown University Lombardi Comprehensive Cancer Center, Washington D.C., United States of America., Department of Internal Medicine, Fox Chase Cancer Center, Philadelphia, United States of America., Department of Pathology, Fox Chase Cancer Center, Philadelphia, United States of America., Medical School, University of Minnesota, Minneapolis, United States of America., Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, United States of America., Department of Molecular Biology, Caris LifeSciences, Irving, United States of America., Chairman of the Caris Precision Oncology Alliance, Caris LifeSciences, Phoenix, United States of America., Moores Cancer Center, UCSD, San Diego, United States of America.