title: PDGFRA activating mutations in gastrointestinal stromal tumors.
abstract: Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
authors.affiliation: Department of Medicine, Department of Pathology, Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, OR 97201, USA. heinrich@ohsu.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Anette
authors.initials: A
authors.lastname: Duensing
authors.forename: Laura
authors.initials: L
authors.lastname: McGreevey
authors.forename: Chang-Jie
authors.initials: CJ
authors.lastname: Chen
authors.forename: Nora
authors.initials: N
authors.lastname: Joseph
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Griffith
authors.forename: Andrea
authors.initials: A
authors.lastname: Haley
authors.forename: Ajia
authors.initials: A
authors.lastname: Town
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000818:Animals; D016466:CHO Cells; D002869:Chromosome Aberrations; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005091:Exons; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009857:Oncogenes; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases