Master Regulators Associated with Poor Prognosis in Glioblastoma Multiforme

Glioblastoma multiforme is a highly malignant brain tumor with average survival time of 15 months. Less than 2% of the patients survive beyond 36 months. To understand the molecular mechanism responsible for poor prognosis, we analyzed GBM samples of TCGA microarray (n = 560) data. We identified 720 genes that have a significant impact upon survival based on univariate cox regression. We applied the Genome Enhancer pipeline to analyze potential mechanisms of regulation of activity of these genes and to build gene regulatory networks. We identified 12 transcription factors enriched in the promoters of these genes including the key molecule of GBM—STAT3. We found that STAT3 has significant differential expression across extreme survivor groups (short-term survivors– survival < 12 months and long-term survivors—survival > 36 months) and also has significant impact on survival. In the next step, we identified master regulators in the signal transduction network that regulate the activity of these transcription factors. Master regulators are filtered based on their differential expression across extreme survivor groups and impact on survival. This work validates our earlier report on master regulators IGFBP2, PDGFA, OSMR and AEBP1 driving short survival. Additionally, we propose CD14, CD44, DUSP6, GRB10, IL1RAP, FGFR3 and POSTN as master regulators driving poor survival. These master regulators are proposed as promising therapeutic targets to counter poor prognosis in GBM. Finally, the algorithm has prioritized several drugs for the further study as potential remedies to conquer the aggressive forms of GBM and to extend survival of the patients.