Proteogenomic Analysis Identifies Clinically Relevant Subgroups of Collecting Duct Carcinoma

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Abstract
Collecting duct carcinoma (CDC) is a rare but aggressive form of renal cell carcinoma (RCC) that has limited understanding and an undefined systemic therapeutic regimen. Herein, we conducted a comprehensive proteogenomic analysis of CDC tumors and normal adjacent tissues to elucidate the biology of the disease. CDC exhibited high heterogeneity in tumor mutational burden, and enhanced ribosome biogenesis was the most striking malignant feature of CDC, even compared with other common kidney carcinomas. Genomic data indicated that UTP6 and HN1 amplification on chromosome 17q were associated with the activations of ribosome biogenesis and cell migration, respectively, which were relevant to tumor proliferation and metastasis. Proteomic-based classification identified 3 clusters, among which, tumors overexpressing ribosome biogenesis signaling (GP1) clustered into the most aggressive subtype, while tumors with increased energy metabolism (GP3) exhibited significant sensitivity to anti-vascular endothelial growth factor agents. Immune subtyping revealed a complex immune landscape of CDC. Additionally, increased RPF2, contributing to ribosome production, was validated to be associated with malignant phenotypes, and targeting RPF2 could exert an anti-oncogenic role by disrupting ribosome biogenesis and perturbing the MDM2–p53 interaction.
Funding Information
  • Key Technologies Research and Development Program (2022YFA1303200)
  • Key Technologies Research and Development Program (2022YFA1303201)
  • Key Technologies Research and Development Program (2023YFC2505900)
  • National Natural Science Foundation of China (32330062)
  • National Natural Science Foundation of China (31972933)
  • National Natural Science Foundation of China (82172817)
  • National Natural Science Foundation of China (82172741)
  • National Natural Science Foundation of China (82473192)
  • National Natural Science Foundation of China (32201215)
  • Program of Shanghai Academic Research Leader (22XD1420100)
  • Major Projects of Special Development Funds in Zhangjiang National Independent Innovation Demonstration Zone, Shanghai (ZJ2019-ZD-004)
  • Shanghai Rising-Star Program (23QA1408900)
  • Shanghai Municipal Health Bureau (2020CXJQ03)
  • Science and Technology Commission of Shanghai Municipality (2023SHZDZX02)

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