eprintid: 22044
rev_number: 15
eprint_status: archive
userid: 1589
dir: disk0/00/02/20/44
datestamp: 2016-10-26 13:15:06
lastmod: 2016-11-07 12:35:40
status_changed: 2016-10-26 13:15:06
type: article
metadata_visibility: show
creators_name: Jungk, Christine
creators_name: Mock, Andreas
creators_name: Exner, Janina
creators_name: Geisenberger, Christoph
creators_name: Warta, Rolf
creators_name: Capper, David
creators_name: Abdollahi, Amir
creators_name: Friauf, Sara
creators_name: Lahrmann, Bernd
creators_name: Grabe, Niels
creators_name: Beckhove, Philipp
creators_name: von Deimling, Andreas
creators_name: Unterberg, Andreas
creators_name: Herold-Mende, Christel
title: Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone
subjects: 610
divisions: 716000
divisions: 850300
divisions: 911200
divisions: 911400
divisions: 911800
divisions: 912000
abstract: 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.
date: 2016
publisher: BioMed Central; Springer
id_scheme: DOI
id_number: http://dx.doi.org/10.1186/s12916-016-0710-7
ppn_swb: 1653741988
own_urn: urn:nbn:de:bsz:16-heidok-220444
language: eng
bibsort: JUNGKCHRISSPATIALTRA2016
full_text_status: public
publication: BMC Medicine
volume: 14
number: 170
place_of_pub: London; Berlin; Heidelberg
pagerange: 1-16
issn: 1741-7015
citation:   Jungk, Christine ; Mock, Andreas ; Exner, Janina ; Geisenberger, Christoph ; Warta, Rolf ; Capper, David ; Abdollahi, Amir ; Friauf, Sara ; Lahrmann, Bernd ; Grabe, Niels ; Beckhove, Philipp ; von Deimling, Andreas ; Unterberg, Andreas ; Herold-Mende, Christel  (2016) Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone.  BMC Medicine, 14 (170).  pp. 1-16.  ISSN 1741-7015     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/22044/1/12916_2016_Article_710.pdf