Multi-Platform Classification of IDH-Wild-Type Glioblastoma Based on ERK/MAPK Pathway: Diagnostic, Prognostic and Therapeutic Implications

SIMPLE SUMMARY: This study presents a unified classification of glioblastoma that streams multi-platform data from genomic, transcriptomic, histologic, and demographic analyses into targetable glioblastoma subgroups connected by signaling through canonical growth pathways. This structured and clear analysis addresses the current needs of neuro-oncological practice and offers practical guidelines for the diagnosis, prognosis, and therapeutic targeting of glioblastoma, being thus of great benefit to both patients and brain tumor practitioners alike. ABSTRACT: Glioblastoma is the most aggressive and frequent glioma in the adult population. Because current therapy regimens confer only minimal survival benefit, molecular subgrouping to stratify patient prognosis and therapy design is warranted. This study presents a multi-platform classification of glioblastoma by analyzing a large, ethnicity-inclusive 101-adult-patient cohort. It defines seven non-redundant IDH-wild-type glioblastoma molecular subgroups, G1–G7, corresponding to the upstream receptor tyrosine kinase (RTK) and RAS-RAF segment of the ERK/MAPK signal transduction pathway. These glioblastoma molecular subgroups are classified as G1/EGFR, G2/FGFR3, G3/NF1, G4/RAF, G5/PDGFRA, G6/Multi-RTK, and G7/Other. The comprehensive genomic analysis was refined by expression landscaping of all RTK genes, as well as of the major associated growth pathway mediators, and used to hierarchically cluster the subgroups. Parallel demographic, clinical, and histologic pattern analyses were merged with the molecular subgrouping to yield the first inclusive multi-platform classification for IDH-wild-type glioblastoma. This straightforward classification with diagnostic and prognostic significance may be readily used in neuro-oncological practice and lays the foundation for personalized targeted therapy approaches.