Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.
The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
Roel G W
RG
Verhaak
Katherine A
KA
Hoadley
Elizabeth
E
Purdom
Victoria
V
Wang
Yuan
Y
Qi
Matthew D
MD
Wilkerson
C Ryan
CR
Miller
Li
L
Ding
Todd
T
Golub
Jill P
JP
Mesirov
Gabriele
G
Alexe
Michael
M
Lawrence
Michael
M
O'Kelly
Pablo
P
Tamayo
Barbara A
BA
Weir
Stacey
S
Gabriel
Wendy
W
Winckler
Supriya
S
Gupta
Lakshmi
L
Jakkula
Heidi S
HS
Feiler
J Graeme
JG
Hodgson
C David
CD
James
Jann N
JN
Sarkaria
Cameron
C
Brennan
Ari
A
Kahn
Paul T
PT
Spellman
Richard K
RK
Wilson
Terence P
TP
Speed
Joe W
JW
Gray
Matthew
M
Meyerson
Gad
G
Getz
Charles M
CM
Perou
D Neil
DN
Hayes
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005163:Factor Analysis, Statistical; D018628:Gene Dosage; D015870:Gene Expression; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha