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PMID: 20889717 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Genes & development ·Vol. 24 ·No. 19 ·2010-10-01 ·Pages 2205-18

Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y, Tandon A, Fomchenko EI, Oka H, Levine RL, Fujii K, Ladanyi M, Holland EC

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 PDGFRA(Δ8, 9), an intragenic deletion rearrangement. The PDGFRA(Δ8, 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.

MeSH Terms
Amino Acid Sequence Base Sequence Benzamides Gene Dosage Gene Fusion/genetics Gene Rearrangement Glioblastoma/genetics,pathology Humans Imatinib Mesylate Mitogen-Activated Protein Kinases/metabolism Molecular Sequence Data Mutation/genetics Oligodendroglioma/genetics,pathology Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Phthalazines/pharmacology Piperazines/pharmacology Protein Kinase Inhibitors/pharmacology Protein-Tyrosine Kinases/genetics,metabolism Pyridines/pharmacology Pyrimidines/pharmacology Receptor, Platelet-Derived Growth Factor alpha/genetics,metabolism Signal Transduction Transformation, Genetic/drug effects
Chemicals
Benzamides Phthalazines Piperazines Protein Kinase Inhibitors Pyridines Pyrimidines vatalanib Imatinib Mesylate Phosphatidylinositol 3-Kinases Protein-Tyrosine Kinases Receptor, Platelet-Derived Growth Factor alpha Mitogen-Activated Protein Kinases
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Ozawa Tatsuya
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Brennan Cameron W
Wang Lu
Squatrito Massimo
Sasayama Takashi
Nakada Mitsutoshi
Huse Jason T
Pedraza Alicia
Utsuki Satoshi
Yasui Yoshie
Tandon Adesh
Fomchenko Elena I
Oka Hidehiro
Levine Ross L
Fujii Kiyotaka
Ladanyi Marc
Holland Eric C
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.1972310
Published
2010-10-01
Pages
2205-18
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2947772
Subset
IM
Grants
NCI NIH HHS · R01 CA100688 · United States
NCI NIH HHS · UO1CA04002 · United States
External Links
PubMed source DOI: 10.1101/gad.1972310 PMC Full Text View journal details
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