Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme.
KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs) are important clinical targets for tyrosine kinase inhibitors. The frequency of KIT and VEGFR2 amplification in glioblastomas is not known, and few data are available in any other human tumour type. We investigated 43 primary glioblastomas for KIT, VEGFR2, PDGFRA and EGFR amplification using fluorescence in situ hybridization. KIT was amplified in 47% and VEGFR2 in 39% of the glioblastomas, respectively, and PDGFRA in 29%. Thirty-five (81%) of the tumours had either KIT or EGFR amplification. KIT, PDGFRA and VEGFR2 amplifications were strongly associated (p < 0.0001 for each pairwise comparison), suggesting co-amplification, whereas no significant association was found with EGFR amplification. The four secondary glioblastomas arising from pre-existing lower grade astrocytic tumours investigated had KIT amplification but none had EGFR amplification. No mutations were detected with denaturing high-performance liquid chromatography in KIT exons 9, 11, 13 or 17, PDGFRA exons 12 and 18, or EGFR exons 18, 19 or 21. Glioblastomas with KIT, PDGFR or VEGFR2 amplification were associated with similar outcome to other glioblastomas. We conclude that KIT, PDGFRA and VEGFR2 are commonly amplified in primary glioblastoma and that they may also be amplified in secondary glioblastoma. Amplified kinases may be potential targets for tyrosine kinase inhibitor therapy.
Joensuu
Heikki
H
Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. heikki.joensuu@hus.fi
Puputti
Marjut
M
Sihto
Harri
H
Tynninen
Olli
O
Nupponen
Nina N
NN
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D042783:Endothelial Cells / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D018773:Genes, erbB-1 / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D016019:Survival Analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040301:Vascular Endothelial Growth Factor Receptor-2