4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29577-x

Keywords

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Funding

  1. National Program on Key Basic Research Project [2019YFA0801900, 2019YFC1316000]
  2. National Key R&D Program of China [2017YFA0505102, 2016YFA0502500, 2018YFE0201603, 2017YFA0505101, 2020YFE0201600, 2019YFC1316005]
  3. National Natural Science Foundation of China [31770886, 31972933, 81802525, 82172817, 81872099, 82172741]
  4. Natural Science Foundation of Shanghai [20ZR1413100]
  5. Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
  6. Major Project of Special Development Funds of Zhangjiang National Independent innovation Demonstration Zone [ZJ2019-ZD-004]
  7. China Postdoctoral Science Foundation [2020T130114]
  8. Fudan original research personalized support project
  9. Shanghai Rising Stars of Medical Talent Youth Medical Talents-Specialist Program

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This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.
Clear cell renal cell carcinoma is an aggressive form of renal cancer, with differences in genomic mutations reported between Western and Eastern populations. In this study, the authors have compiled proteogenomic analysis of Chinese ccRCC to reveal genomic alterations and dysregulation of immune and metabolic responses. 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.

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