Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs.
Histopathology
; 55(1): 53-62, 2009 Jul.
Article
em En
| MEDLINE
| ID: mdl-19614767
ABSTRACT
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 ANDRESULTS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas Proto-Oncogênicas c-kit
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Quinases de Proteína Quinase Ativadas por Mitógeno
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Receptor alfa de Fator de Crescimento Derivado de Plaquetas
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Tumores do Estroma Gastrointestinal
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Neoplasias Gastrointestinais
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Mutação
Tipo de estudo:
Diagnostic_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article