Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma

Nat Genet. 2014 May;46(5):457-461. doi: 10.1038/ng.2925. Epub 2014 Apr 6.


Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / genetics*
  • Base Sequence
  • Brain Stem Neoplasms / classification
  • Brain Stem Neoplasms / genetics*
  • Child
  • Cohort Studies
  • Exome / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genome, Human / genetics*
  • Glioma / classification
  • Glioma / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Myositis Ossificans / genetics
  • Sequence Analysis, DNA
  • Signal Transduction / genetics


  • ACVR1 protein, human
  • Activin Receptors, Type I