The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

Nat Genet. 2014 May;46(5):444-450. doi: 10.1038/ng.2938. Epub 2014 Apr 6.

Abstract

Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / genetics*
  • Animals
  • Brain Stem Neoplasms / genetics*
  • Child
  • Cohort Studies
  • Computational Biology
  • Gene Expression Profiling
  • Gene Fusion / genetics
  • Glioma / genetics*
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Microarray Analysis
  • Receptor, trkA / genetics
  • Receptor, trkB / genetics
  • Receptor, trkC / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • Statistics, Nonparametric
  • Zebrafish

Substances

  • Receptor, trkA
  • Receptor, trkB
  • Receptor, trkC
  • ACVR1 protein, human
  • Activin Receptors, Type I