BAP1 loss defines a new class of renal cell carcinoma

Nat Genet. 2012 Jun 10;44(7):751-9. doi: 10.1038/ng.2323.

Abstract

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Cell Growth Processes / physiology
  • Cells, Cultured
  • Exome
  • Female
  • Gene Expression / genetics
  • Host Cell Factor C1 / genetics
  • Host Cell Factor C1 / metabolism
  • Humans
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Interaction Domains and Motifs
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / deficiency*
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism

Substances

  • BAP1 protein, human
  • HCFC1 protein, human
  • Host Cell Factor C1
  • Nuclear Proteins
  • PBRM1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase

Supplementary concepts

  • Clear-cell metastatic renal cell carcinoma

Associated data

  • GEO/GSE25540
  • GEO/GSE36895