TY  - JOUR
JF  - BMC Medicine
ID  - heidok22044
AV  - public
TI  - Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone
SP  - 1
PB  - BioMed Central; Springer
EP  - 16
VL  - 14
Y1  - 2016///
IS  - 170
SN  - 1741-7015
CY  - London; Berlin; Heidelberg
N2  - Background: The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers.   Methods: mRNA microarray data of a discovery set (n?=?36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore? workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis.   Results: Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas?s molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p?=?0.034; HR 1.55) and DLL3 (p?=?0.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p?=?0.049; HR 0.66) and PIR (p?=?0.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p?=?0.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p?=?0.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p?=?0.046; HR 1.65).   Conclusions: We identified four genes with SVZ-dependent expression and prognostic significance, among those HES4 and DLL3 as part of Notch signaling, suggesting further evaluation of location-tailored targeted therapies.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/22044/
A1  - Jungk, Christine
A1  - Mock, Andreas
A1  - Exner, Janina
A1  - Geisenberger, Christoph
A1  - Warta, Rolf
A1  - Capper, David
A1  - Abdollahi, Amir
A1  - Friauf, Sara
A1  - Lahrmann, Bernd
A1  - Grabe, Niels
A1  - Beckhove, Philipp
A1  - von Deimling, Andreas
A1  - Unterberg, Andreas
A1  - Herold-Mende, Christel
ER  -