A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population
Yuanyuan Qu, Jinwen Feng, Xiaohui Wu, Lin Bai, Wenhao Xu, Lingli Zhu, Yang Liu, Fujiang Xu, Xuan Zhang, Guojian Yang, Jiacheng Lv, Xiuping Chen, Guohai Shi, Hongkai Wang, Dalong Cao, Xiang Hang, Lingling Li, Subei Tan, Hualei Gan, Menghong Sun, Jian‐Ge Qiu, Hailiang Zhang, Jian‐Yuan Zhao, Dingwei Ye, Chen Ding
Abstract
Clear cell renal cell carcinoma (ccRCC) is a common 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 an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1-3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to 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 ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.