Journal
ACTA NEUROPATHOLOGICA
Volume 124, Issue 3, Pages 439-447Publisher
SPRINGER
DOI: 10.1007/s00401-012-0998-0
Keywords
DIPG; H3.3; ATRX; TP53; Survival; Targeted therapy
Categories
Funding
- Canadian Institutes of Health Research (CIHR [MOP 115004]
- Cole Foundation
- Genome Canada/CIHR grant
- Genome BC
- Genome Quebec
- CIHR-ICR (Institute for Cancer Research)
- ICGC project PedBrain Tumor [108456]
- Bundesministerium fur Bildung und Forschung (BMBF)
- Deutsche Krebshilfe
- Foundation of Stars
- CIHR
- Chercheur Boursier Award from Fonds de Recherche en Sante du Quebec
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Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.
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