Papadakos SP, Mandrakis G, Siakavellas SI, Memos N, Gakiopoulou H, Schizas D, Theocharis S. Epigenetic landscape of gastrointestinal stromal tumors: Mechanistic insights and therapeutic opportunities. World J Gastroenterol 2026; 32(17): 118502 [DOI: 10.3748/wjg.v32.i17.118502]
Corresponding Author of This Article
Stavros P Papadakos, MD, Doctor, First Academic Department of Gastroenterology, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Agiou Thoma 17, Athens 11527, Greece. stavrospapadakos@gmail.com
Research Domain of This Article
Gastroenterology & Hepatology
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Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. May 7, 2026; 32(17): 118502 Published online May 7, 2026. doi: 10.3748/wjg.v32.i17.118502
Epigenetic landscape of gastrointestinal stromal tumors: Mechanistic insights and therapeutic opportunities
Stavros P Papadakos, Georgios Mandrakis, Spyros I Siakavellas, Nikolaos Memos, Hara Gakiopoulou, Dimitrios Schizas, Stamatios Theocharis
Stavros P Papadakos, First Academic Department of Gastroenterology, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
Stavros P Papadakos, Georgios Mandrakis, Hara Gakiopoulou, Stamatios Theocharis, First Department of Pathology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
Spyros I Siakavellas, Second Academic Department of Internal Medicine, Liver-GI Unit, General Hospital of Athens “Hippocration”, National and Kapodistrian University of Athens, Athens 11527, Greece
Nikolaos Memos, First Department of Propaedeutic Surgery, “Hippokratio” General Hospital, Medical School of Athens National and Kapodistrian University of Athens, Athens 11527, Greece
Dimitrios Schizas, First Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
Co-corresponding authors: Stavros P Papadakos and Stamatios Theocharis.
Author contributions: Papadakos SP and Theocharis S contributed to conceptualization; Papadakos SP and Mandrakis G contributed to data curation; Papadakos SP, Mandrakis G and Siakavellas SI contributed to investigation; Papadakos SP contributed to methodology and writing original draft; Memos N contributed to validation and clinical interpretation; Gakiopoulou H, Schizas D and Theocharis S contributed to supervision; all authors contributed to writing, review and editing.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Corresponding author: Stavros P Papadakos, MD, Doctor, First Academic Department of Gastroenterology, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Agiou Thoma 17, Athens 11527, Greece. stavrospapadakos@gmail.com
Received: January 4, 2026 Revised: January 29, 2026 Accepted: February 13, 2026 Published online: May 7, 2026 Processing time: 110 Days and 18.2 Hours
Abstract
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.
Core Tip: Gastrointestinal stromal tumors (GISTs) are driven primarily by KIT or PDGFRA mutations, yet therapeutic resistance and heterogeneous clinical behavior remain major challenges. This review highlights how epigenetic mechanisms DNA methylation, histone modifications, and chromatin remodeling shape GIST initiation, progression, and treatment response. We synthesize preclinical and clinical evidence linking epigenetic alterations to prognosis, resistance, and emerging therapeutic vulnerabilities, and discuss how chromatin-directed strategies may complement tyrosine kinase inhibition to advance precision oncology in GIST.
