Distinct Phenotypic Differences Associated with Differential Amplification of Receptor Tyrosine Kinase Genes at 4q12 in Glioblastoma

<div><p>Gene amplification at chromosome 4q12 is a common alteration in human high grade gliomas including glioblastoma, a CNS tumour with consistently poor prognosis. This locus harbours the known oncogenes encoding the receptor tyrosine kinases <i>PDGFRA</i>, <i>KIT</i>, and <i>VEGFR2</i>. These receptors are potential targets for novel therapeutic intervention in these diseases, with expression noted in tumour cells and/or associated vasculature. Despite this, a detailed assessment of their relative contributions to different high grade glioma histologies and the underlying heterogeneity within glioblastoma has been lacking. We studied 342 primary high grade gliomas for individual gene amplification using specific FISH probes, as well as receptor expression in the tumour and endothelial cells by immunohistochemistry, and correlated our findings with specific tumour cell morphological types and patterns of vasculature. We identified amplicons which encompassed <i>PDGFRA</i> only, <i>PDGFRA/KIT</i>, and <i>PDGFRA/KIT/VEGFR2</i>, with distinct phenotypic correlates. Within glioblastoma specimens, <i>PDGFRA</i> amplification alone was linked to oligodendroglial, small cell and sarcomatous tumour cell morphologies, and rare <i>MGMT</i> promoter methylation. A younger age at diagnosis and better clinical outcome in glioblastoma patients is only seen when <i>PDGFRA</i> and <i>KIT</i> are co-amplified. <i>IDH1</i> mutation was only found when all three genes are amplified; this is a subgroup which also harbours extensive <i>MGMT</i> promoter methylation. Whilst <i>PDGFRA</i> amplification was tightly linked to tumour expression of the receptor, this was not the case for <i>KIT</i> or <i>VEGFR2.</i> Thus we have identified differential patterns of gene amplification and expression of RTKs at the 4q12 locus to be associated with specific phenotypes which may reflect their distinct underlying mechanisms.</p>