Amplification of genes encoding KIT, PDGFRα and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme

Abstract

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.

Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide

“…The majority of AEs that led to discontinuation were considered a consequence of disease progression. [3][4] AEs that occurred in more than 5% of patients in any group.…”

“…2 In GBM, EGFR and PDGFR are amplified in approximately 50% 2 and 21% of patients, respectively. 3 All attempts to prolong the length of PFS and OS using biological agents such as thalidomide, melatonin, cis/trans retinoic acids, or gene therapy did not significantly improve prognosis.…”

Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas

“…PDGF receptors and their ligands have an established role in the development and progression of human gliomas: gene amplification and overexpression of PDGFRA are found in up to 33% of malignant gliomas 22,23 and might stimulate tumor growth by autocrine PDGF receptor signaling. 12,13 In a recent study on pediatric gliomas, PDGFRA was found to be amplified in 2 out of 14 malignant gliomas but not in any of the low-grade tumors examined.…”

Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

“…This deletion results in an in-frame deletion of 81 aa in the extracellular domain in PDGFRA (37) and has subsequently been shown to be oncogenic (38). PDGFRA is also implicated in glioblastomas by the reports of a few cases of glioblastoma in which the PDGFRA gene is amplified (37,(39)(40)(41)(42), leading to receptor overexpression. High levels of PDGFRA expression, possibly independent of genomic amplification, are found in tumors without EGFR gene amplification (43).…”