gms | German Medical Science

Objective: We have recently reported that spatial relationship of primary glioblastomas (pGBMs) to the subventricular zone (SVZ), the predominant neurogenic region of the adult brain, is associated with inferior patient survival and significantly increased protein expression of neural stem cell (NSC) markers, suggesting location-dependent differences in the clinical behavior and stem cell phenotype of pGBMs. We therefore hypothesized that there are distinctive location-dependent gene expression patterns shedding further light into the molecular heterogeneity of pGBM.

Method: RNA was extracted from histologically confirmed vital tumor samples of 29 pGBMs differing in their spatial relationship to the SVZ (SVZ contact: n=12; no SVZ contact: n=17) and utilized for mRNA microarray analysis (Illumina^® HumanHT-12 v4 Expression Bead Chip). Data processing and statistical analysis was carried out employing R statistical computing software. Pathway analysis was conducted using MetaCore™ software.

Results: mRNA microarray analysis was able to identify gene expression patterns that distinguish pGBMS contacting the SVZ from pGBMs without contact to the SVZ. Hierarchical clustering revealed 94 genes with a significance level of p<0.01 and 579 genes with a significance level of p<0.05, among those being CD133, one of the NSC markers applied in our protein expression analysis, which was significantly overexpressed in pGBMs contacting the SVZ. Metacore™ pathway analysis of the top 579 differentially expressed genes identified pathways associated with immune responses (lymphocyte proliferation, T-cell receptor signaling), developmental and Notch signaling, angiogenesis and the actin cytoskeleton to be the most differentially expressed pathways in pGBMs with respect to their spatial relationship to the SVZ.

Conclusions: In this study, mRNA expression data strongly support our initial findings that spatial relationship of pGBMs to the SVZ significantly impacts on the clinical course and a stem cell-related phenotype. Gene expression patterns of tumors with or without contact to the SVZ differ significantly in major pathways associated with gliomagenesis, suggesting an outstanding role of tumor location with presumably different cells of origin that contribute to the molecular heterogeneity of pGBMs. Further analysis is under way to validate and functionally characterize the most promising candidate genes.