Low frequency of MAP kinase pathway alterations inKITandPDGFRAwild-type GISTs

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.