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. 2009 Jul;55(1):53-62.
doi: 10.1111/j.1365-2559.2009.03323.x.

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

Olga Martinho  1 , António Gouveia, Marta Viana-Pereira, Paula Silva, Amadeu Pimenta, Rui Manuel Reis, José Manuel Lopes
Affiliations

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

Olga Martinho et al. Histopathology. 2009 Jul.

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.

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