Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.
Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany.
Dominik
D
Sturm
Hendrik
H
Witt
Volker
V
Hovestadt
Dong-Anh
DA
Khuong-Quang
David T W
DT
Jones
Carolin
C
Konermann
Elke
E
Pfaff
Martje
M
Tönjes
Martin
M
Sill
Sebastian
S
Bender
Marcel
M
Kool
Marc
M
Zapatka
Natalia
N
Becker
Manuela
M
Zucknick
Thomas
T
Hielscher
Xiao-Yang
XY
Liu
Adam M
AM
Fontebasso
Marina
M
Ryzhova
Steffen
S
Albrecht
Karine
K
Jacob
Marietta
M
Wolter
Martin
M
Ebinger
Martin U
MU
Schuhmann
Timothy
T
van Meter
Michael C
MC
Frühwald
Holger
H
Hauch
Arnulf
A
Pekrun
Bernhard
B
Radlwimmer
Tim
T
Niehues
Gregor
G
von Komorowski
Matthias
M
Dürken
Andreas E
AE
Kulozik
Jenny
J
Madden
Andrew
A
Donson
Nicholas K
NK
Foreman
Rachid
R
Drissi
Maryam
M
Fouladi
Wolfram
W
Scheurlen
Andreas
A
von Deimling
Camelia
C
Monoranu
Wolfgang
W
Roggendorf
Christel
C
Herold-Mende
Andreas
A
Unterberg
Christof M
CM
Kramm
Jörg
J
Felsberg
Christian
C
Hartmann
Benedikt
B
Wiestler
Wolfgang
W
Wick
Till
T
Milde
Olaf
O
Witt
Anders M
AM
Lindroth
Jeremy
J
Schwartzentruber
Damien
D
Faury
Adam
A
Fleming
Magdalena
M
Zakrzewska
Pawel P
PP
Liberski
Krzysztof
K
Zakrzewski
Peter
P
Hauser
Miklos
M
Garami
Almos
A
Klekner
Laszlo
L
Bognar
Sorana
S
Morrissy
Florence
F
Cavalli
Michael D
MD
Taylor
Peter
P
van Sluis
Jan
J
Koster
Rogier
R
Versteeg
Richard
R
Volckmann
Tom
T
Mikkelsen
Kenneth
K
Aldape
Guido
G
Reifenberger
V Peter
VP
Collins
Jacek
J
Majewski
Andrey
A
Korshunov
Peter
P
Lichter
Christoph
C
Plass
Nada
N
Jabado
Stefan M
SM
Pfister
D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006657:Histones / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009154:Mutation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D059467:Transcriptome
D006657:Histones; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha