K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.
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.
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Dong-Anh
DA
Khuong-Quang
Pawel
P
Buczkowicz
Patricia
P
Rakopoulos
Xiao-Yang
XY
Liu
Adam M
AM
Fontebasso
Eric
E
Bouffet
Ute
U
Bartels
Steffen
S
Albrecht
Jeremy
J
Schwartzentruber
Louis
L
Letourneau
Mathieu
M
Bourgey
Guillaume
G
Bourque
Alexandre
A
Montpetit
Genevieve
G
Bourret
Pierre
P
Lepage
Adam
A
Fleming
Peter
P
Lichter
Marcel
M
Kool
Andreas
A
von Deimling
Dominik
D
Sturm
Andrey
A
Korshunov
Damien
D
Faury
David T
DT
Jones
Jacek
J
Majewski
Stefan M
SM
Pfister
Nada
N
Jabado
Cynthia
C
Hawkins
D000293:Adolescent; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006657:Histones / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D011149:Pons / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate
D006657:Histones