Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO

Science. 2013 Mar 1;339(6123):1077-80. doi: 10.1126/science.1233009. Epub 2013 Jan 24.

Abstract

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / classification
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Chromosomes, Human, Pair 22 / genetics
  • DNA Mutational Analysis
  • Female
  • Genes, Neurofibromatosis 2
  • Genomic Instability
  • Genomics
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Male
  • Meningeal Neoplasms / classification
  • Meningeal Neoplasms / genetics*
  • Meningeal Neoplasms / pathology
  • Meningioma / classification
  • Meningioma / genetics*
  • Meningioma / pathology
  • Middle Aged
  • Mutation
  • Neoplasm Grading
  • Proto-Oncogene Proteins c-akt / genetics*
  • Receptors, G-Protein-Coupled / genetics*
  • Smoothened Receptor
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics*

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Receptors, G-Protein-Coupled
  • SMO protein, human
  • Smoothened Receptor
  • TRAF7 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt