BACKGROUND: Translating findings on the genomic landscape of metastatic clear-cell renal cell carcinoma (mccRCC) into clinical practice remains challenging. A better understanding of the molecular features of mccRCC could identify a prognostic and/or predictive role for ccRCC genomic alterations. PATIENTS AND METHODS: In this real-world observational study based on the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine, Inc. clinico-genomic database (FH-FMI-CGDB), we investigate the frequency and co-occurrence of genomic alterations in mccRCC patients and assess their prognostic role. Patients (n = 858) were adults diagnosed with mccRCC, with FH electronic health records between 2011 and 2022. RESULTS: The top 10 mutated genes were VHL (73.9%), PBRM1 (42.4%), SETD2 (25.3%), CDKN2A (20.0%), BAP1 (16.4%), CDKN2B (16.0%), KDM5C (14.5%), TP53 (12.9%), PTEN (11.7%), and TERT (9.2%). Eight genes showed prognostic value: CDKN2A, CDKN2B, TP53, PTEN, NF2, PIK3CA, and MTAP were linked to worse prognosis, whereas PBRM1 was associated with better overall survival (OS). Two of the three identified gene clusters had prognostic value: cluster 1 (VHL, SETD2, PBRM1, KDM5C, NFE2L2) correlated with better OS [adjusted hazard ratio (aHR) 0.63, P <
0.001], whereas cluster 3 (CDKN2A, CDKN2B, BAP1, NF2, MTAP) correlated with shorter OS (aHR 1.36, P = 0.023). CONCLUSION: We identified eight genes and two gene clusters with prognostic significance for mccRCC. Future research will explore the predictive value of gene clusters in various treatments.