Molecular profiling of long-term survivors identifies a subgroup of glioblastoma characterized by chromosome 19/20 co-gain.
Glioblastoma (GBM) is a devastating tumor and few patients survive beyond 3 years. Defining the molecular determinants underlying long-term survival is essential for insights into tumor biology and biomarker identification. We therefore investigated homogeneously treated, IDH (wt) long-term (LTS, n = 10) and short-term survivors (STS, n = 6) by microarray transcription profiling. While there was no association of clinical parameters and molecular subtypes with long-term survival, STS tumors were characterized by differential polarization of infiltrating microglia with predominance of the M2 phenotype detectable both on the mRNA and protein level. Furthermore, transcriptional signatures of LTS and STS predicted patient outcome in a large, IDH (wt) cohort (n = 468). Interrogation of overlapping genomic alterations identified concurrent gain of chromosomes 19 and 20 as a favorable prognostic marker. The strong association of this co-gain with survival was validated by aCGH in a second, independent cohort (n = 124). Finally, FISH and gene expression data revealed gains to constitute low-amplitude, clonal events with a strong impact on transcription. In conclusion, these findings provide important insights into the manipulation of the innate immune system by particularly aggressive GBM tumors. Furthermore, we genomically characterize a previously unknown, clinically relevant subgroup of glioblastoma, which can easily be identified through modern neuropathological workup.
Division of Experimental Neurosurgery, Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Christoph
C
Geisenberger
Andreas
A
Mock
Rolf
R
Warta
Carmen
C
Rapp
Christian
C
Schwager
Andrey
A
Korshunov
Ann-Katrin
AK
Nied
David
D
Capper
Benedikt
B
Brors
Christine
C
Jungk
David
D
Jones
V Peter
VP
Collins
Koichi
K
Ichimura
L Magnus
LM
Bäcklund
Elena
E
Schnabel
Michel
M
Mittelbron
Bernd
B
Lahrmann
Siyuan
S
Zheng
Roel G W
RG
Verhaak
Niels
N
Grabe
Stefan M
SM
Pfister
Christian
C
Hartmann
Andreas
A
von Deimling
Jürgen
J
Debus
Andreas
A
Unterberg
Amir
A
Abdollahi
Christel
C
Herold-Mende
D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002888:Chromosomes, Human, Pair 19; D002890:Chromosomes, Human, Pair 20; D015331:Cohort Studies; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis; D017741:Survivors; D013997:Time Factors; D014158:Transcription, Genetic
D012333:RNA, Messenger; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human