title: Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. christine.jungk@med.uni-heidelberg.de.
authors: Christine
authors: C
authors: Jungk
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Andreas
authors: A
authors: Mock
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Janina
authors: J
authors: Exner
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Christoph
authors: C
authors: Geisenberger
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Rolf
authors: R
authors: Warta
authors: Department of Neuropathology, Heidelberg University Hospital; CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: David
authors: D
authors: Capper
authors: 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.
authors: Amir
authors: A
authors: Abdollahi
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Sara
authors: S
authors: Friauf
authors: Hamamatsu Tissue and Imaging Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors: Bernd
authors: B
authors: Lahrmann
authors: Hamamatsu Tissue and Imaging Analysis Center, University of Heidelberg, Heidelberg, Germany.
authors: Niels
authors: N
authors: Grabe
authors: Division of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Regensburg Center for Interventional Immunology (RCI), University Hospital, Regensburg, Germany.
authors: Philipp
authors: P
authors: Beckhove
authors: Department of Neuropathology, Heidelberg University Hospital; CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Andreas
authors: A
authors: von Deimling
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Andreas
authors: A
authors: Unterberg
authors: Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors: Christel
authors: C
authors: Herold-Mende
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D020547:Lateral Ventricles / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D051880:Receptors, Notch; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Glioblastoma; Location-dependent prognostic markers; Notch signaling; Subventricular zone; mRNA microarray analysis