A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma

Nat Genet. 2014 Apr;46(4):371-5. doi: 10.1038/ng.2916. Epub 2014 Mar 2.

Abstract

The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly17Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly17Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly17Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Comparative Genomic Hybridization
  • Exome / genetics
  • Gene Silencing*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lymphoma, T-Cell / genetics*
  • Models, Biological
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Protein Binding
  • Sequence Analysis, RNA
  • Signal Transduction / genetics*
  • Transcriptome / genetics
  • rhoA GTP-Binding Protein / chemistry
  • rhoA GTP-Binding Protein / genetics*

Substances

  • RHOA protein, human
  • rhoA GTP-Binding Protein

Associated data

  • SRA/SRP029591