Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness

Clinical Proteomic Tumor Analysis Consortium

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

Original languageEnglish
Pages (from-to)139-163.e17
JournalCancer Cell
Volume41
Issue number1
DOIs
StatePublished - 9 Jan 2023

Keywords

  • CPTAC
  • UCHL1
  • clear cell renal cell carcinoma
  • glycoproteomics
  • histology
  • metabolome
  • phosphoproteomics
  • proteogenomics
  • single-nuclei RNA-seq
  • tumor heterogeneity

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