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BMC Med. 2016 Oct 26;14(1):170.

Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone.

Author information

1
Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. christine.jungk@med.uni-heidelberg.de.
2
Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
3
Department of Neuropathology, Heidelberg University Hospital; CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Department of Radiation Oncology, Heidelberg University Hospital; Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Hamamatsu Tissue and Imaging Analysis Center, University of Heidelberg, Heidelberg, Germany.
6
Division of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Regensburg Center for Interventional Immunology (RCI), University Hospital, Regensburg, Germany.

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.

KEYWORDS:

Glioblastoma; Location-dependent prognostic markers; Notch signaling; Subventricular zone; mRNA microarray analysis

PMID:
27782828
PMCID:
PMC5080721
DOI:
10.1186/s12916-016-0710-7
[Indexed for MEDLINE]
Free PMC Article

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