Genetic Analysis of Diffuse High-Grade Astrocytomas in Infancy Defines a Novel Molecular Entity

Brain Pathol. 2015 Jul;25(4):409-17. doi: 10.1111/bpa.12210. Epub 2014 Dec 19.


Pediatric high-grade gliomas are considered to be different when compared to adult high-grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high-grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high-grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe-dependent amplification (MLPA), pyrosequencing of glioma-associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high-grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high-grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior.

Keywords: ALT; ATRX; H3F3A; SNORD; glioblastoma; high-grade glioma; infants; molecular inversion probe analysis; multiplex ligation probe-dependent amplification; pediatric brain tumors.

MeSH terms

  • Adolescent
  • Astrocytoma / classification
  • Astrocytoma / genetics*
  • Astrocytoma / pathology
  • Brain Neoplasms / classification
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Child
  • Child, Preschool
  • Chromosome Aberrations*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Helicases / metabolism
  • Female
  • Histones / genetics
  • Humans
  • Immunohistochemistry
  • Infant
  • Male
  • Multiplex Polymerase Chain Reaction
  • Mutation
  • Nuclear Proteins / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Telomerase / genetics
  • X-linked Nuclear Protein


  • Cyclin-Dependent Kinase Inhibitor p16
  • Histones
  • Nuclear Proteins
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Telomerase
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein