In patients with gastrointestinal stromal tumors (GIST), it has become mandatory to determine the driver mutation in order to predict the response to standard treatment with tyrosine kinase inhibitors (TKI). A total of 10‑15% of all GIST lack activating mutations in KIT proto‑oncogene, receptor tyrosine kinase (KIT)/platelet‑derived growth factor receptor alpha (PDGFRA) and have been classified as KIT/PDGFRA wild‑type (WT) GIST. They are characterized by poor response to TKI. From a group of 119 metastatic GIST patients, 17 patients with KIT/PDGFRA/BRAF WT GIST as determined by reverse transcription‑quantitative (RT‑q) PCR and Sanger sequencing were profiled by a targeted next‑generation sequencing (NGS) approach and their treatment outcome was assessed. In the present study, 41.2% of patients as KIT/PDGFRA/BRAF WT GIST examined with RT‑qPCR and Sanger sequencing were confirmed to be carriers of pathogenic KIT/PDGFRA mutations by NGS and were responsive to TKI. The percentage of genuinely KIT/PDGFRA WT GIST in the present study thereby dropped from the initial 14.3% detected with the RT‑qPCR and Sanger sequencing to 7.6% after NGS. Their outcome was universally poor. The reliability of RT‑qPCR and direct Sanger sequencing results in this setting is therefore insufficient and it is recommended that NGS becomes a requirement for treatment decision at least in KIT/PDGFRA/BRAF WT GIST as determined by RT‑qPCR and Sanger sequencing.
Keywords: gastrointestinal stromal tumors; imatinib; next‑generation sequencing; tyrosine kinase inhibitors; wild‑type.