From Genes to Proteins: The Indispensable Role of Proteogenomics in Advancing Clear Cell Renal Cell Carcinoma Research

Clear cell renal cell carcinoma (ccRCC) is characterized by a complex molecular landscape driven by recurrent genetic alterations. While genomic and transcriptomic profiling have identified core drivers, they often fail to provide robust biomarkers due to the significant decoupling of mRNA and protein levels, as well as the critical role of post-translational modifications in tumor biology. This review synthesizes current evidence from landmark proteogenomic initiatives, such as the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and independent multi-omic studies. It evaluates the integration of genomic, transcriptomic, and proteomic data to map metabolic reprogramming, signalling pathway activity, and chromatin-level alterations in ccRCC. Proteogenomic analyses reveal that protein-level data provide a functional perspective that is missing from sequencing alone, specifically identifying suppressed oxidative phosphorylation, enhanced glycolysis, and the activation of the PI3K/AKT/mTOR cascade, independent of genetic mutations. Furthermore, proteogenomics has defined novel molecular subtypes and individual protein biomarkers, such as UCHL1 and p-mTOR, which correlate more accurately with clinical outcomes and therapeutic responses than their transcriptomic counterparts. Proteogenomics is a crucial tool for refining disease taxonomy and identifying novel therapeutic vulnerabilities in ccRCC. By bridging the gap between genotype and functional phenotype, this integrated approach facilitates more precise risk stratification and accelerates the development of personalized medicine through better-informed selection of targeted and immune-based therapies.