Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas

J Pathol. 2009 Jun;218(2):172-81. doi: 10.1002/path.2558.


We report genetic aberrations that activate the ERK/MAP kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high frequency of gene fusions between KIAA1549 and BRAF among these tumours. These fusions were identified from analysis of focal copy number gains at 7q34, detected using Affymetrix 250K and 6.0 SNP arrays. PCR and sequencing confirmed the presence of five KIAA1549-BRAF fusion variants, along with a single fusion between SRGAP3 and RAF1. The resulting fusion genes lack the auto-inhibitory domains of BRAF and RAF1, which are replaced in-frame by the beginning of KIAA1549 and SRGAP3, respectively, conferring constitutive kinase activity. An activating mutation of KRAS was identified in the single pilocytic astrocytoma without a BRAF or RAF1 fusion. Further fusions and activating mutations in BRAF were identified in 28% of grade II astrocytomas, highlighting the importance of the ERK/MAP kinase pathway in the development of paediatric low-grade gliomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Astrocytoma / enzymology*
  • Astrocytoma / genetics
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • DNA, Complementary / analysis
  • Enzyme Activation
  • GTPase-Activating Proteins / genetics
  • Humans
  • Infant
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-raf / genetics
  • Young Adult


  • DNA, Complementary
  • GTPase-Activating Proteins
  • Oncogene Proteins, Fusion
  • SRGAP3 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases