Integrated molecular analysis of clear-cell renal cell carcinoma

Nat Genet. 2013 Aug;45(8):860-7. doi: 10.1038/ng.2699. Epub 2013 Jun 24.


Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which ≥100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C-VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / mortality
  • Cell Line
  • Cluster Analysis
  • DNA Copy Number Variations
  • DNA Methylation
  • Elongin
  • Exome
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / mortality
  • Mutation
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • ELOC protein, human
  • Elongin
  • Hypoxia-Inducible Factor 1
  • Transcription Factors