Role of Mutations in Gastrointestinal Stromal Tumors

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Understanding GIST mutational patterns is fundamental for personalized treatment approaches in GIST care. Approximately 85% to 90% of GISTs are driven by gain-of-function mutations in KIT or PDGFR genes, with KIT exon 11 mutations being most responsive to first-line imatinib therapy. However, 10% to 15% of patients harbor alternative genetic alterations, including SDH-deficient GIST, BRAF mutations, NF1 alterations, or NTRK fusions. The distinction between primary mutations (present at diagnosis) and secondary mutations (developing during treatment) directly impacts therapeutic decision-making and patient outcomes.

Secondary resistance mutations pose significant challenges in GIST treatment, typically developing in the adenosine triphosphate–binding pocket (exons 13-14) or activation loop (exons 17-18) of the KIT gene. Some tumors develop resistance mutations in both locations simultaneously, creating complex treatment scenarios. The D842V mutation in PDGFR-alpha represents a particularly challenging primary resistance pattern to imatinib, requiring alternative therapeutic approaches. Understanding these resistance mechanisms is crucial for sequencing treatments and developing combination strategies to prevent or overcome drug resistance.

Mutational analysis serves both prognostic and predictive functions in GIST management. Wild-type patients (lacking KIT and PDGFR-alpha mutations) often exhibit more indolent disease biology, while mutated tumors tend toward more aggressive behavior. The clinical utility primarily lies in predictive applications, where specific mutations guide kinase inhibitor selection. For instance, KIT exon 9 mutations may require higher imatinib doses, while PDGFR-alpha D842V mutations necessitate alternative targeted agents such as avapritinib, highlighting the critical importance of comprehensive molecular profiling before treatment initiation.