Recurrent Somatic Alterations of FGFR1 and NTRK2 in Pilocytic Astrocytoma

Nat Genet. 2013 Aug;45(8):927-32. doi: 10.1038/ng.2682. Epub 2013 Jun 30.

Abstract

Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.

Publication types

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

MeSH terms

  • Animals
  • Astrocytoma / genetics*
  • Astrocytoma / metabolism
  • Base Sequence
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Chromosome Breakpoints
  • Chromosomes, Human, Pair 6
  • Chromosomes, Human, Pair 9
  • Fibroblast Growth Factors / metabolism
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Models, Molecular
  • Mutation*
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / genetics
  • Protein Conformation
  • Proto-Oncogene Proteins B-raf / chemistry
  • Proto-Oncogene Proteins B-raf / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, trkB / genetics*
  • Receptor, trkB / metabolism

Substances

  • Oncogene Proteins, Fusion
  • Fibroblast Growth Factors
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, trkB
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf