Abstract
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are generally characterized by driver mutations in KIT or PDGFRA. However, the molecular landscape of wild-type GISTs remains complex, posing significant therapeutic challenges. Recent evidence has indicated alterations in FGFR2 as potential oncogenic drivers in patients with various cancers. However, the role of these drivers in GIST pathogenesis remains underexplored. CASE SUMMARY: We retrospectively evaluated two patients with GIST, diagnosed between August 2021 and July 2022, harboring FGFR2 mutations through hybrid capture-based next-generation sequencing (NGS). We analyzed their clinicopathological characteristics, treatment response, and long-term follow-up data. Both patients, a 47-year-old man (case 1) and a 43-year-old woman (case 2), underwent successful surgical resection and received adjuvant imatinib therapy. They achieved sustained remission with a median follow-up of 28 months. Notably, the NGS revealed novel FGFR2 rearrangements, an FGFR2-CIT/intergenic-FGFR2 fusion in case 1 and FGFR2-CAMK2G/FGFR2-VCL fusions in case 2 without canonical KIT or PDGFRA mutations. Both patients exhibited a favorable response to standard imatinib treatment. CONCLUSION: Our findings provided preliminary evidence that novel FGFR2 fusions might act as primary oncogenic drivers in a rare subset of KIT/PDGFRA wild-type GISTs. These cases highlight the importance for comprehensive genomic profiling and suggest that fibroblast growth factor receptor-targeted inhibitors could be a potential therapeutic strategy for advanced or imatinib-resistant diseases, warranting further investigation in larger cohorts.