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

Table 4 Histone modifications as diagnostic, prognostic, and predictive tools in gastrointestinal stromal tumors[41,50,52,54-56,60-62,64]

Ref.	Patient cohort/clinical role	Methodology	Key findings
Jin et al[60]	119 primary GISTs/diagnostic	IHC, digital quantification	PHH3 counts correlated strongly with mitotic index and NIH risk category improved reproducibility compared with conventional mitotic figures
Huang et al[56]	134 patients (discovery: 18 tumors from 14 patients; prevalence validation: 125 tumors from 120 patients; 89 high-risk/metastatic, 34 low/intermediate-risk)/prognostic	Exome + targeted resequencing (KIT/PDGFRA/SETD2); H3K36me3 IHC; 450K methylation array; RNA-sequencing	SETD2 mutations in 11.2% (10/89) of high-risk and 0% (0/34) of low/intermediate-risk GISTs gastric SETD2-mutant tumors show hypomethylated heterochromatin and reduced H3K36me3; associated with shorter relapse-free survival
Shen et al[54]	48 GISTs, paired tumor vs adjacent tissue/diagnostic/prognostic	IHC, ChIP-qPCR	KDM6A and SPARCL1 correlated with mitotic index, risk classification, and metastatic recurrence. Diagnostic ROC analysis: AUC: 0.698 (KDM6A), 0.834 (SPARCL1), 0.858 (EZH2). Low KDM6A linked to higher metastasis rates and reduced survival
Ji et al[55]	46 GIST tumors with matched adjacent tissue; stratified by NIH risk (low/intermediate/high)/diagnostic/prognostic	IHC, molecular assays	Tumors showed SMYD2 and EZH2 upregulation with H3K27me3 increase and TET1 downregulation; high-risk cases enriched for this profile
Niinuma et al[41]	131 primary GISTs, validation in 44 tumors/prognostic	Methylation assays, ChIP	MEG3 hypermethylation associated with higher recurrence risk (HR = 2.3; 95%CI: 1.2-4.6) altered H3K4me3 linked to poor recurrence-free survival
Qiu et al[52]	26 paired GIST tumors vs adjacent tissues/prognostic	IHC, tissue analysis	miR-409-5p expression is decreased in GIST tumors compared to adjacent normal tissues. Lower miR-409-5p levels correlate with higher GIST risk grade
Gao et al[64]	67 WT GIST patients/prognostic	IHC, tissue studies	SDHB deficiency: Higher ZNF148 expression, significantly shorter PFS (median approximately 104 months vs not reached). High ZNF148-pS306: Inferior PFS. SDHB deficiency = independent predictor of shorter PFS
Wang et al[50]	9 GISTs (3 low-, 3 moderate-, 3 high-risk)/prognostic	Mass spectrometry	Identified 2904 acetyl sites on 1319 proteins (quantified 2548 sites on 1169 proteins) vs low risk, 42 sites (38 proteins) up and 48 sites (44 proteins) down in high/moderate risk. Largest shifts: Ki67 K1063Ac (increase), FCHSD2 K24Ac (decrease)
Yen et al[61]	Public microarray datasets (including GIST samples with exon 11 mutations) compared to other sarcoma subtypes; validation on patient-derived GIST tissues/translational	Connectivity map + tissue validation	ETV1, along with KIT, DOG1, and PKCθ, was significantly overexpressed in GIST patient samples compared to multiple sarcoma subtypes; phenothiazines (trifluoperazine, thioridazine) emerged as candidate ETV1-targeting agents with potential for biomarker-guided drug repositioning
Zeng et al[62]	Twelve matched pairs of GIST resections from the same patients, taken pre-imatinib and after adjuvant imatinib with subsequent relapse/predictive	IHC, paired tissue analysis	IHC on paired samples revealed that BCL6 expression was consistently elevated after imatinib treatment in the 12 patient pairs, linking its upregulation with resistance and recurrence, and suggesting a rationale for combining BCL6 inhibition with imatinib therapy

GIST: Gastrointestinal stromal tumors; WT: Wild-type; NIH: National Institutes of Health; IHC: Immunohistochemistry; ChIP: Chromatin immunoprecipitation; qPCR: Quantitative polymerase chain reaction; ROC: Receiver operating characteristic; AUC: Area under the curve; HR: Hazard ratio; CI: Confidence interval; SDHB: Succinate dehydrogenase subunit B; PFS: Progression-free survival; PKC: Protein kinase C.