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

Abstract

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 PDGFRA, KIT, and VEGFR2. 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 PDGFRA only, PDGFRA/KIT, and PDGFRA/KIT/VEGFR2, with distinct phenotypic correlates. Within glioblastoma specimens, PDGFRA amplification alone was linked to oligodendroglial, small cell and sarcomatous tumour cell morphologies, and rare MGMT promoter methylation. A younger age at diagnosis and better clinical outcome in glioblastoma patients is only seen when PDGFRA and KIT are co-amplified. IDH1 mutation was only found when all three genes are amplified; this is a subgroup which also harbours extensive MGMT promoter methylation. Whilst PDGFRA amplification was tightly linked to tumour expression of the receptor, this was not the case for KIT or VEGFR2. 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.

Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

“…1p/19q codeleted tumors tend to activate the PI3K/mTOR or Ras intracellular signaling pathways and TP53 -mutant tumors tend to amplify growth factor receptor tyrosine kinases. Our findings are consistent with prior reports; recurrent PIK3CA mutations have been detected in a subset of IDH -mutant, 1p/19q codeleted anaplastic oligodendrogliomas (7, 26) and two recent reports observed enrichment of PDGFRA amplification in IDH -mutant versus IDH -wildtype primary GBM (27, 41). In addition, we find that activation of N-myc may be a particularly malignant transformation pathway in IDH -mutant glioma.…”

Involvement of platelet‐derived growth factor ligands and receptors in tumorigenesis

“…The PDGFRA gene is located on chromosome 4q12, close to KIT and KDR , which are often present in the same amplicon as PDGFRA . Interestingly, only PDGFRA shows a clear correlation between gene amplification and level of expression , suggesting that the selective advantage conferred by the 4q12 amplicon is mainly provided by PDGFRA . Molecular profiling of GBM has defined aberration of the PDGFRα pathway as a denominator of the proneural subgroup of GBM, occurring both in tumours with and without IDH1/2 mutations.…”

The Three Receptor Tyrosine Kinases c-KIT, VEGFR2 and PDGFRα, Closely Spaced at 4q12, Show Increased Protein Expression in Triple-Negative Breast Cancer

“…In this study, gene copy number and protein expression were evaluated for three RTKs as potential breast cancer drug targets: c-KIT, vascular endothelial growth factor receptor-2 (VEGFR2) and PDGFRα. The genes c-KIT , VEGFR2 and PDGFRα are all adjacently located at the 4q12 chromosomal segment and their involvement in the cancer process have been investigated in various malignancies, such as for example gliomas [20] – [22] , malignant peripheral nerve sheath tumors [23] and GISTs [24] . However, to date, their role in breast cancer remains largely unknown.…”