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

Dong Anh Khuong-Quang, Pawel Buczkowicz, Patricia Rakopoulos, Xiao Yang Liu, Adam M. Fontebasso, Eric Bouffet, Ute Bartels, Steffen Albrecht, Jeremy Schwartzentruber, Louis Letourneau, Mathieu Bourgey, Guillaume Bourque, Alexandre Montpetit, Genevieve Bourret, Pierre Lepage, Adam Fleming, Peter Lichter, Marcel Kool, Andreas Von Deimling, Dominik SturmAndrey Korshunov, Damien Faury, David T. Jones, Jacek Majewski, Stefan M. Pfister, Nada Jabado, Cynthia Hawkins

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

707 Citaten (Scopus)


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. Wildtype 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. K27MH3.3 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.

Originele taal-2Engels
Pagina's (van-tot)439-447
Aantal pagina's9
TijdschriftActa Neuropathologica
Nummer van het tijdschrift3
StatusGepubliceerd - sep. 2012
Extern gepubliceerdJa


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