Epigenetic landscape of gastrointestinal stromal tumors: Mechanistic insights and therapeutic opportunities

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are primarily driven by activating mutations in KIT or PDGFRA . A clinically important subset of KIT /PDGFRA wild-type GISTs harbors alterations affecting succinate dehydrogenase subunit genes, which are associated with distinct biology and epigenetic profiles. The introduction of tyrosine kinase inhibitors has transformed their management, yet resistance and recurrence remain major challenges. Increasing evidence indicates that epigenetic processes contribute to tumor initiation, progression, and therapeutic escape. Aberrant promoter methylation has been linked to silencing of tumor suppressor genes, histone modifications reshape transcriptional networks governing proliferation and apoptosis, and chromatin remodeling complexes influence lineage-specific transcription and resistance pathways. Clinical observations further demonstrate that alterations such as SETD2 loss, KDM6A downregulation, or PHH3 overexpression correlate with prognosis, while early-phase trials of histone deacetylase inhibitors illustrate therapeutic feasibility. This review synthesizes current preclinical and clinical evidence on epigenetic regulation in GIST, focusing on DNA methylation, histone modifications, and chromatin remodeling, and explores their translational implications for prognosis and therapy.