A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population

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.

DPP9 Overexpression in Clear Cell Renal Cell Carcinoma Causes Ferroptosis Suppression and Sorafenib Resistance Through the KEAP1–NRF2 Pathway

“…A similar trend was observed in a large-scale proteomic analysis of 213 ccRCC specimens from a Chinese FUSCC cohort (Supplementary Fig. 1B) [17] .…”

“…We also obtained RNA-seq data of 91 ccRCC patients from ICGC database ( https://icgc.org/). The DPP9 protein level of normal and tumor tissues was also analyzed from a largescale proteomic analysis of 213 ccRCC in a Chinese population [17] .…”

Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma

“…Interestingly, in the Chinese population, ccRCC, the most common and malignant subtype of RCC, exhibits distinct proteomic characteristics and immune phenotypes 27 . Increasing evidence suggests that the malignant behaviors and treatment resistance of cancers are heavily governed by the crosstalk between the TME and tumor cells 28 .…”

Deciphering the role of miR-187-3p/LRFN1 axis in modulating progression, aerobic glycolysis and immune microenvironment of clear cell renal cell carcinoma

“…Currently, ccRCC is characterized by its heterogeneous and complex tumor microenvironment (TME), and it is difficult to identify high-risk patients for recurrence after therapeutic nephrectomy due to uncertain description of intra-tumoral heterogeneity and lack of effective biomarkers [8][9][10]. Considering high morbidity and mortality of ccRCC, it is critical to reveal the causes of aggressive malignancy and explore molecular biomarkers for early diagnosis, prognostic prediction and guiding personalized treatment strategies [11].…”