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

Abstract

BackgroundThe 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.MethodsmRNA 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.ResultsMicroarray 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).ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0710-7) contains supplementary material, which is available to authorized users.

Identification of Potential Key Genes Associated with the Pathogenesis and Prognosis of Glioblastoma Based on Integrated Bioinformatics Analysis

“…[101] As for PIR, it has been identified as a protective prognostic gene and been reported that high expression of PIR (p = 0.025, HR 0.62 (0.41-0.95); Q1 cut-off) predicts superior overall survival of GBM patients based on univariate analysis. [102] However, unlike the previous study, our results suggest that high expression of PIR (p = 0.018, HR 1.089(1.015-1.168)) predicts inferior overall survival of GBM patients. This discrepancy may lie in the reasons as follows: 1 The limitations of our study were as follows: (1) we performed our study based on integrated bioinformatics analysis, our results need further biological experiments validation.…”

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…55 In IDH wild-type glioblastoma, DLL3 is mainly expressed in the tumor lesions contacting the subventricular zone (SVZ) but not involving the cortex, which is a prognostic marker of poor PFS. 56 However, in high-grade gliomas, DLL3 is defined as a proneural signature gene that is associated with longer survival, with DLL3/Notch signaling a major determinant of tumor growth. 57 In vitro experiments indicate that DLL3 expression is downregulated in glioma cells, the recovery of which can inhibit the survival, proliferation and invasiveness of glioma cells.…”

The role of inflammation in subventricular zone cancer

“…This could explain why periventricular tumors are more likely to be multifocal and present relapses that are not contiguous with the primary site. Finally, tumors in the SVZ have a stem-like profile and are associated with specific genetic alterations that support cell growth, proliferation and survival via altered metabolic programs, centromere assembly, chromosome segregation, epigenetic modifiers and increased ribosomal biogenesis (Haskins et al, 2013;Jungk et al, 2016;Lin et al, 2017).…”