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: ATRX

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 Wild-type versus mutated (K27M-H3.3) subgroups compared HIST1H3B, IDH, ATRX TP53 mutations, copy number alterations outcome. K27M-H3.3 occurred in 71 %, mutations 77 % 9 DIPGs. more frequent older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 identified. showed specific changes, all gains/amplifications PDGFRA MYC/PVT1 loci. Notably, long-term survivors wild type this group patients had better overall survival. mutation defines clinically biologically distinct is prevalent DIPG, which will impact future therapeutic trial design. K27M- G34V-H3.3 have location-based incidence (brainstem/cortex) potentially play roles pediatric GBM pathogenesis. universally associated short survival while wild-type show improved Based on prognostic implications, our findings argue H3.3-mutation testing at diagnosis, should be rapidly integrated into the decision-making algorithm, particularly atypical DIPG.