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

Table 3 Predictive biomarkers of DNA methylation in gastrointestinal stromal tumors[42,78,83-85]

Ref.	Cohort/samples	Targets	Methodology	Key findings
Giger et al[78]	SDH-deficient cohorts	MGMT promoter	MSP	MGMT methylation enriched in SDH-deficient GIST; suggested biomarker for temozolomide sensitivity
Ricci et al[83]	74 cases	MGMT promoter	MSP	Confirmed MGMT methylation in SDH-deficient/WT tumors (67% vs 15%); advocated alkylator trials with stratification
Italiano et al[84]	Imatinib-resistant cases	IGF2/IGF1R deregulation	Epigenetic expression analysis	Epigenetic activation of IGF axis implicated in imatinib resistance
Urbini et al[85]	Quadruple WT vs SDH-deficient	FGF4	Genomic vs methylation	In SDH-deficient, FGF4 induced by methylation; in WT, due to duplication. Suggested FGFR inhibitors
Xu et al[42]	53 cases (tissue)	METTL3-MRP1 (RNA methylation)	m6A + functional assays	High METTL3 expression linked to shorter PFS in resistant patients; RNA methylation mechanism of imatinib resistance

MRP1: Multidrug resistance protein 1; GIST: Gastrointestinal stromal tumors; WT: Wild-type; SDH: Succinate dehydrogenase; MGMT: O-6-methylguanine-DNA methyltransferase; IGF2: Insulin-like growth factor 2; IGF1R: Insulin-like growth factor 1 receptor; FGF: Fibroblast growth factor; m6A: N6-methyladenosine; MSP: Methylation-specific polymerase chain reaction; PFS: Progression-free survival; FGFR: Fibroblast growth factor receptor.