PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

  1. Eric C. Holland1,2,10,11
  1. 1Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  2. 2Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  3. 3Department of Neurosurgery and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  4. 4Department of Pathology and Human Oncology, Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  5. 5Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan;
  6. 6Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan;
  7. 7Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan;
  8. 8Department of Neurosurgery, The Albert Einstein College of Medicine, Bronx, New York 10467, USA;
  9. 9Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  10. 10Department of Surgery, Neurosurgery, and Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    Abstract

    Gene rearrangement in the form of an intragenic deletion is the primary mechanism of oncogenic mutation of the epidermal growth factor receptor (EGFR) gene in gliomas. However, the incidence of platelet-derived growth factor receptor-α (PDGFRA) gene rearrangement in these tumors is unknown. We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements, including the first case of a gene fusion between kinase insert domain receptor (KDR) (VEGFRII) and the PDGFRA gene, and six cases of PDGFRAΔ8, 9, an intragenic deletion rearrangement. The PDGFRAΔ8, 9 mutant was common, being present in 40% of the glioblastoma multiformes (GBMs) with PDGFRA amplification. Tumors with these two types of PDGFRA rearrangement displayed histologic features of oligodendroglioma, and the gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated.

    Keywords

    Footnotes

    • Received July 20, 2010.
    • Accepted August 17, 2010.
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