A Proteogenomic Atlas of Clear Cell Renal Cell Carcinoma in a Chinese Population

Clear cell renal cell carcinoma (ccRCC) is a majority and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and intensive immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1–3), among which the most aggressive GP1 exhibit dominant immune response, metastasis, and metabolic imbalance, linking the proteomic features, transcription factor activities, genomic alterations, and clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes tumor growth in ccRCC. This study provides valuable insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.