Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin.
OBJECTIVE
Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1(R132MUT)) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1(R132MUT) differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1(R132) mutation status.


METHODS
In all, 618 treatment-naive primary GBMs and 235 lower-grade diffuse gliomas were sequenced for IDH1(R132) and analyzed for demographic, radiographic, anatomic, histologic, genomic, epigenetic, and transcriptional characteristics.


RESULTS
Investigation revealed a constellation of features that distinguishes IDH1(R132MUT) GBMs from other GBMs (including frontal location and lesser extent of contrast enhancement and necrosis), relates them to lower-grade IDH1(R132MUT) gliomas, and supports the concept that IDH1(R132MUT) gliomas arise from a neural precursor population that is spatially and temporally restricted in the brain. The observed patterns of DNA sequence, methylation, and copy number alterations support a model of ordered molecular evolution of IDH1(R132MUT) GBM in which the appearance of mutant IDH1 protein is an initial event, followed by production of p53 mutant protein, and finally by copy number alterations of PTEN and EGFR.


CONCLUSIONS
Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.
David Geffen School of Medicine at theUniversity of California at Los Angeles, Los Angeles, CA, USA.
Albert
A
Lai
Samir
S
Kharbanda
Whitney B
WB
Pope
Anh
A
Tran
Orestes E
OE
Solis
Franklin
F
Peale
William F
WF
Forrest
Kanan
K
Pujara
Jose A
JA
Carrillo
Ajay
A
Pandita
Benjamin M
BM
Ellingson
Chauncey W
CW
Bowers
Robert H
RH
Soriano
Nils O
NO
Schmidt
Sankar
S
Mohan
William H
WH
Yong
Somasekar
S
Seshagiri
Zora
Z
Modrusan
Zhaoshi
Z
Jiang
Kenneth D
KD
Aldape
Paul S
PS
Mischel
Linda M
LM
Liau
Cameron J
CJ
Escovedo
Weidong
W
Chen
Phioanh Leia
PL
Nghiemphu
C David
CD
James
Michael D
MD
Prados
Manfred
M
Westphal
Katrin
K
Lamszus
Timothy
T
Cloughesy
Heidi S
HS
Phillips
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D016158:Genes, p53; D005909:Glioblastoma / Q000235:genetics*; D005910:Glioma / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human