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

Abstract

Background: A high heterogeneity and activation of multiple oncogenic pathways have been implicated in failure of targeted therapies in glioblastoma (GBM). Methods: Using The Cancer Genome Atlas 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 8 combined public datasets containing 608 GBMs. We further examined prognostic chromosome aberrations and mutations. Results: In classical and mesenchymal subtypes, 2 receptor tyrosine kinases (RTKs) (MET and IGF1R), and the genes in RTK downstream pathways such as phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and nuclear factor-kappaB (NF-kB), were commonly detected as prognostic core genes. Classical subtype-specific prognostic core genes included those in cell cycle, DNA repair, and the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway. Immune-related genes were enriched in the prognostic genes showing negative promoter cytosine-phosphate-guanine (CpG) methylation/expression correlations. Mesenchymal subtype-specific prognostic genes were those related to mesenchymal cell movement, PI3K/Akt, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), Wnt/β-catenin, and Wnt/Ca2+ pathways. In copy number alterations and mutations, 6p loss and TP53 mutation were associated with poor and good survival, respectively, in the classical subtype. In the mesenchymal subtype, patients with PIK3R1 or PCLO mutations showed poor prognosis. In the glioma CpG island methylator phenotype (G-CIMP) subtype, patients harboring 10q loss, 12p gain, or 14q loss exhibited poor survival. Furthermore, 10q loss was significantly associated with the recently recognized G-CIMP subclass showing relatively low CpG methylation and poor prognosis. Conclusion: These subtype-specific alterations have promising potentials as new prognostic biomarkers and therapeutic targets combined with surrogate markers of GBM subtypes. However, considering the small number of events, the results of copy number alterations and mutations require further validations.