O.M. and A.G. contributed equally to this work.
Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs
Article first published online: 9 JUL 2009
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Limited
Volume 55, Issue 1, pages 53–62, July 2009
How to Cite
Martinho, O., Gouveia, A., Viana-Pereira, M., Silva, P., Pimenta, A., Reis, R. M. and Lopes, J. M. (2009), Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs. Histopathology, 55: 53–62. doi: 10.1111/j.1365-2559.2009.03323.x
- Issue published online: 9 JUL 2009
- Article first published online: 9 JUL 2009
- Date of submission 10 July 2008 Accepted for publication 16 December 2008
- MAP kinase;
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.