title: Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs.
abstract: OBJECTIVE
  Gastrointestinal stromal tumours (GISTs) are commonly driven by oncogenic mutations in KIT and PDGFRA. However, 10-40% of these patients are wild-type for these genes. The prognostic significance of wild-type GISTs is controversial, and they rarely respond to imatinib. The aim of this study was to elucidate the molecular lesions underlying wild-type GISTs tumorigenesis.
  
  
  RESULTS
  Twenty-nine KIT and PDGFRA wild-type GISTs were re-assessed for the presence of 'cryptic'KIT exon 11 duplications. Using a specific polymerase chain reaction assay, three previously undetected mutations were identified. In the remaining 26 wild-type GISTs, KIT, stem cell factor (SCF), phospho-KIT and phospho-ERK expression was evaluated by immunohistochemistry. Samples were screened for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade. KIT and SCF co-expression associated with KIT activation was observed in approximately 30% of cases. Furthermore, phospho-ERK expression showed that MAPK is activated in approximately 30% of cases. None of RAS family (H-, K- and N-RAS) oncogenes exhibited activating mutations, whereas BRAF mutations were found in approximately 4% of cases.
  
  
  CONCLUSIONS
  In the absence of RAS mutations, MAPK could be activated through SCF/KIT autocrine/paracrine mechanisms and/or mutated BRAF in a subset of KIT/PDGFRA wild-type GISTs.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: Olga
authors.initials: O
authors.lastname: Martinho
authors.forename: António
authors.initials: A
authors.lastname: Gouveia
authors.forename: Marta
authors.initials: M
authors.lastname: Viana-Pereira
authors.forename: Paula
authors.initials: P
authors.lastname: Silva
authors.forename: Amadeu
authors.initials: A
authors.lastname: Pimenta
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Reis
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)