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- Title
Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs.
- Authors
Martinho, Olga; Gouveia, António; Viana-Pereira, Marta; Silva, Paula; Pimenta, Amadeu; Reis, Rui Manuel; Lopes, José Manuel
- 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 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.
- Subjects
GASTROINTESTINAL stromal tumors; GASTROINTESTINAL tumors treatment; PROTEIN kinases; ONCOGENIC viruses; POLYMERASE chain reaction; IMMUNOHISTOCHEMISTRY; TUMOR treatment; THERAPEUTICS
- Publication
Histopathology, 2009, Vol 55, Issue 1, p53
- ISSN
0309-0167
- Publication type
Article
- DOI
10.1111/j.1365-2559.2009.03323.x