Clinicopathological and molecular features of wild-type gastrointestinal stromal tumors identified by targeted NGS.

Wild-type (WT) gastrointestinal stromal tumors (GISTs) are a rare and molecularly heterogeneous subset of GISTs lacking KIT and PDGFRA mutations. These tumors pose significant diagnostic and therapeutic challenges due to resistance to standard tyrosine kinase inhibitors and a wide spectrum of genetic drivers. A total of 156 GIST patients were retrospectively reviewed, among whom 19 WT GIST cases were identified. Immunohistochemistry, Sanger sequencing, and targeted next-generation sequencing (NGS) covering 39 cancer-related genes were performed to evaluate clinicopathological and molecular characteristics. Variants were annotated and filtered using public mutation databases. Among the 19 WT GISTs, 8 (42.1%) harbored additional genetic alterations, including FLT3 (p.R973X), CDH1 (p.D786N), and TERT promoter alterations, along with copy number gain in CCND1 and copy number loss in RB1. SDHA and SDHD mutations were found in SDH-deficient tumors. Immunohistochemical analysis revealed a subset of SDHA-mutated tumors with retained SDHA protein expression. Kaplan-Meier analysis showed a difference in progression-free survival (PFS) between WT and non-WT GISTs (p=0.001); however, this finding should be interpreted with caution due to the small sample size and lack of adjusted analysis. WT GISTs exhibit considerable molecular heterogeneity with novel or rare mutations of uncertain significance. Targeted NGS enables the detection of clinically relevant alterations that may guide future diagnostic and therapeutic strategies. Our findings emphasize the importance of targeted molecular profiling and raise the potential for personalized treatment in this challenging subset of GISTs.