Table 1.
Major Genetic RTK Alterations in GBM
| RTK Alteration | Incidence | Clinical Relevance | Biological Functions |
|---|---|---|---|
| VEGFR2 amplification | VEGFR2 amplification detection varies from 6% to 17%.5 | Increased VEGFR indicates angiogenesis and is associated to meschymal subtype of GBM and poor prognosis.6 | VEGF promotes angiogenesis in GBM but also suppresses tumor cell invasion through a MET/VEGFR2 heterodimerization.7 |
| EGFR amplification | About 45% of GBM have EGFR mutation or amplification.4 | Indicates classical subtype of GBM and is associated to poor prognosis.6,8 | Enhances neurosphere cell line growth in the presence of EGF/FGF.6 |
| EGFRvIII | About 20% of GBM have EGFRvIII or other types of extracellular domain mutations.4 | Controversal. Large-scale studies have not shown EGFRvIII as a prognostic marker for GBM.9,10 | Upregulates DNA mismatch repair and increased sensitivity to TMZ.11 |
| ERBB2 mutation | 8% of GBM have ERBB2 mutation.4 | High expression of ERBB2 associates to shorter survival time in GBM.12 | EGFR depletion activates ERBB2 in GSCs, leading to resistance to EGFR inhibitors.13 |
| PDGFRα amplification | 13% of GBM show PDGFRα amplifications.4 | PDGF signaling indicates the proneural subtype of GBM.6,8 | Overexpression of PDGFRα mutant is associated to gliomagenesis.14,15 |
| PDGFRβ overexpression | PDGFRβ, VEGFR2, PDGFRα, are overexpressed on the majority of endothelial cells in GBM.16 | Overexpression initiates tumors in mice models, and contributes to glioma stem cell growth.17 | |
| MET amplification | About 4% GBM have MET amplification.4 However, 13-30% of GBM have MET overexpression.18,19 | MET overexpression indicates poor prognosis in GBM.20 | Overexpression of HGF/MET axis leads to glioma formation in mice.21 |
| ZM fusion/ METex14 | 15% of secondary GBM have at least one ZM fusion protein.22 About 14% of secondary GBM have MET-exon-14 skipping.23 | ZM fusion plus METex 14 associates to poor prognosis in secondary GBM.23 | Exon 14 skipping removes the juxta-membrane domain of MET, generating cytosolic MET which is constitutively active in a ligand-independent manner but is sensitive to MET inhibitors.23 |
| METΔ7-8 | About 6% of high-grade gliomas, including 3.3% of GBM, have METΔ7-8 mutation.24 | Presence indicates a high-grade glioma.24 | Located predominantly in the cytosol, constitutively active and is sensitive to MET TKI.24 |
| FGFR-TACC fusion | 3% of GBM have an FGFR-TACC fusion protein, with FGFR3 and TACC3 as the most common fusion type (FGFR3-TACC3).25,26 | FGFR3-TACC3 fusions in IDH wild-type glioma indicates sensitivity to FGFR inhibitors.27 | FGFR3-TACC3 fusion protein transforms astrocytes into glioma cells in the mouse brain.25 FGFR-TACC changes metabolism of GBM cells.26 |