K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas

• DOI: 10.1007/s00401-012-0998-0
• Publication Date: 2012-06-04T13:47:31Z
• Authors: Dong-Anh Khuong-Q...; Pawel Buczkowicz; Patricia Rakopoulos; Xiao-Yang Liu; Adam M. Fontebasso; Eric Bouffet; Ute Bartels; Steffen Albrecht; Jeremy Schwartzen...; Louis Letourneau; Mathieu Bourgey; Guillaume Bourque; Alexandre Montpetit; Genevieve Bourret; Pierre Lepage; Adam Fleming; Peter Lichter; Marcel Kool; Andreas von Deimling; Dominik Sturm; Andrey Korshunov; Damien Faury; David T. Jones; Jacek Majewski; Stefan M. Pfister; Nada Jabado; Cynthia Hawkins
• Keywords: Male; Original Paper; 0303 health sciences; Adolescent; Gene Expression Profiling; Clinical Neurology; 610; Infant; Glioma; Prognosis; Pathology and Forensic Medicine; 3. Good health; 618; Histones; Survival Rate; Cellular and Molecular Neuroscience; 03 medical and health sciences; Child, Preschool; Pons; Mutation; Brain Stem Neoplasms; Humans; Female; Child

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.