Molecular Profiling of KIT/PDGFRA-Mutant and Wild-Type Gastrointestinal Stromal Tumors (GISTs) with Clinicopathological Correlation: An 18-Year Experience at a Tertiary Center in Kuwait

In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the <i>KIT/PDGFRA</i> oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the mutational landscape of GISTs and their impact on disease progression are very limited in Kuwait. Using a targeted next-generation sequencing panel, we investigated the spectrum and frequency of <i>KIT</i>, <i>PDGFRA</i>, and RAS-pathway-related mutations in 95 out of 200 GISTs diagnosed at Kuwait Cancer Center from 2005 to 2023 and assessed their correlation with clinicopathological parameters. Among the 200 tumors (median age 55 years; 15-91), 54% originated in the stomach, 33% in the small bowel, 7% in the colorectum, 1.5% in the peritoneum, and 4.5% had an unknown primary site. Of the 95 molecularly profiled cases, 88% had a mutation: <i>KIT</i> (61%), <i>PDGFRA</i> (25%), <i>NF1</i> (2%), and one <i>NTRK1</i> rearrangement. Ten WT-GISTs were identified (stomach = 6, small bowel = 2, and colorectum = 2). WT-GISTs tended to be smaller (median 4.0 cm; 0.5-8.0) (<i>p</i> = 0.018), with mitosis ≤5/5 mm², and were of lower risk (<i>p</i> = 0.019). <i>KIT</i> mutations were an adverse indicator of disease progression (<i>p</i> = 0.049), while wild-type status did not significantly impact progression (<i>p</i> = 0.934). The genetic landscape in this cohort mirrors that of global studies, but regional collaborations are needed to correlate outcomes with genetic variants.