Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development

Hum Mutat. 2012 Jul;33(7):1059-62. doi: 10.1002/humu.22090. Epub 2012 Apr 30.

Abstract

Clear cell renal cell carcinomas are characterized by 3p loss, and by inactivation of Von Hippel Lindau (VHL), a tumorsuppressor gene located at 3p25. Recently, SETD2, located at 3p21, was identified as a new candidate ccRCC tumor-suppressor gene. The combined mutational frequency in ccRCC tumors of VHL and SETD2 suggests that there are still undiscovered tumor-suppressor genes on 3p. We screened all genes on 3p for mutations in 10 primary ccRCC tumors using exome-sequencing. We identified inactivating mutations in VHL, PBRM1, and BAP1. Sequencing of PBRM1 in ccRCC-derived cell lines confirmed its frequent inactivation in ccRCC. PBRM1 encodes for BAF180, the chromatin targeting subunit of the SWI/SNF complex. BAP1 encodes for BRCA1 associated protein-1, involved in histone deubiquitination. Taken together, the accumulating data suggest an important role for aberrant chromatin regulation in ccRCC development.

MeSH terms

  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromosomes, Human, Pair 3 / genetics
  • Exome / genetics*
  • Gene Expression Regulation, Neoplastic / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Nuclear Proteins / genetics
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics

Substances

  • BAP1 protein, human
  • Chromatin
  • Nuclear Proteins
  • PBRM1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Histone-Lysine N-Methyltransferase
  • Set2 protein, human
  • Ubiquitin Thiolesterase