Glioblastoma multiforme: a multi-omics analysis of driver genes and tumour heterogeneity

Abstract

Glioblastoma (GBM) is the most aggressive and common brain cancer in adults with the lowest life expectancy. The current neuro-oncology practice has incorporated genes involved in key molecular events that drive GBM tumorigenesis as biomarkers to guide diagnosis and design treatment. This study summarizes findings describing the significant heterogeneity of GBM at the transcriptional and genomic levels, emphasizing 18 driver genes with clinical relevance. A pattern was identified fitting the stem cell model for GBM ontogenesis, with an upregulation profile for MGMT and downregulation for ATRX, H3F3A, TP53 and EGFR in the mesenchymal subtype. We also detected overexpression of EGFR, NES, VIM and TP53 in the classical subtype and of MKi67 and OLIG2 genes in the proneural subtype. Furthermore, we found a combination of the four biomarkers EGFR, NES, OLIG2 and VIM with a remarkable differential expression pattern which confers them a strong potential to determine the GBM molecular subtype. A unique distribution of somatic mutations was found for the young and adult population, particularly for genes related to DNA repair and chromatin remodelling, highlighting ATRX, MGMT and IDH1. Our results also revealed that highly lesioned genes undergo differential regulation with particular biological pathways for young patients. This multi-omic analysis will help delineate future strategies related to the use of these molecular markers for clinical decision-making in the medical routine.