Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are characterized by mutations in exons 9, 11, 13, and 17 of KIT or exons 12, 14, and 18 of PDGFRA gene. However, approximately 10 to 15 % of GISTs lack the mutations in KIT and PDGFRA, and these are referred to as wild-type GISTs which are less sensitive to tyrosine-kinase inhibitors. The aim of this study was to detect BRAF mutations in patients with wild-type GISTs. We applied a sensitive allele-specific PCR, which was optimized using the V600E mutation-harboring cell line RKO, followed by verification of the results by dideoxy sequencing. We selected 149 GIST patients without detectable mutations in KIT and PDGFRA genes from the Slovak national GIST register and analyzed biopsy specimens for the presence of BRAF mutations in exon 15. We identified nine patients with the V600E mutation. The BRAF-driven GISTs were primary gastric (n = 3), small intestinal (n = 3), colon (n = 1), and of uncertain origin (n = 1). We also included a liver metastasis of a patient with a simultaneous KIT exon 11-mutated intra-abdominal metastasis. We conclude that genome analysis of wild-type GISTs for mutations should include the BRAF gene, as its mutation status contributes to understanding of pathogenesis and might be important for decisions on therapy.