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Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs

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Resumo:Aims: 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. Methods and 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.
Autores principais:Martinho, Olga
Outros Autores:Gouveia, António; Pereira, Marta Sofia Carvalho Ribeiro Viana; Silva, Paula; Pimenta, Amadeu; Reis, R. M.; Lopes, José Manuel
Assunto:Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type
Ano:2009
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso restrito
Instituição associada:Universidade do Minho
Idioma:inglês
Origem:RepositóriUM - Universidade do Minho

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