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.
Verhaak
Roel G W
RG
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
Hoadley
Katherine A
KA
Purdom
Elizabeth
E
Wang
Victoria
V
Qi
Yuan
Y
Wilkerson
Matthew D
MD
Miller
C Ryan
CR
Ding
Li
L
Golub
Todd
T
Mesirov
Jill P
JP
Alexe
Gabriele
G
Lawrence
Michael
M
O'Kelly
Michael
M
Tamayo
Pablo
P
Weir
Barbara A
BA
Gabriel
Stacey
S
Winckler
Wendy
W
Gupta
Supriya
S
Jakkula
Lakshmi
L
Feiler
Heidi S
HS
Hodgson
J Graeme
JG
James
C David
CD
Sarkaria
Jann N
JN
Brennan
Cameron
C
Kahn
Ari
A
Spellman
Paul T
PT
Wilson
Richard K
RK
Speed
Terence P
TP
Gray
Joe W
JW
Meyerson
Matthew
M
Getz
Gad
G
Perou
Charles M
CM
Hayes
D Neil
DN
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