Subtype-specific signaling pathways and genomic aberrations associated with prognosis of glioblastoma.

Background: A high heterogeneity and activation of multiple oncogenic pathways have been implicated in failure of targeted therapies in glioblastoma.

Methods: Using TCGA data, we identified subtype-specific prognostic core genes by a combined approach of genome-wide Cox regression and Gene Set Enrichment Analysis. The results were validated with combined eight public datasets containing 608 glioblastomas. We further examined prognostic chromosome aberrations and mutations.

Results: In Classical and Mesenchymal subtypes, two receptor tyrosine kinases (RTK) (MET and IGF1R), and the genes in RTK downstream pathways such as PI3K/AKT/mTOR, and NF-κB, were commonly detected as prognostic core genes. Classical subtype-specific prognostic core genes included those in cell cycle, DNA repair, and JAK-STAT pathway. Immune-related genes were enriched in the prognostic genes showing negative promoter CpG methylation/expression correlations. Mesenchymal subtype-specific prognostic genes were those related to mesenchymal cell movement, PI3K/AKT, MAPK/ERK, WNT/β-catenin, and WNT/Ca2+ pathways. In copy number alterations and mutations, 6p loss and TP53 mutations were associated with poor and good survival respectively in Classical subtype. In Mesenchymal subtype, patients with PIK3R1 or PCLO mutations showed poor prognosis. In G-CIMP subtype, patients harboring 10q loss, 12p gain, or 14q loss exhibited poor survival. Furthermore, 10q loss was significantly associated with recently recognized G-CIMP subclass showing relatively low CpG methylation and poor prognosis.

Conclusions: These subtype-specific alterations have promising potentials of new prognostic biomarkers and therapeutic targets combined with surrogate markers of glioblastoma subtypes. However, considering the small number of events, the results of copy number alterations and mutations require further validations.