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

Table 1 Diagnostic applications of DNA methylation in gastrointestinal stromal tumors[70-72,74-78]

Ref.	Cohort/samples	Targets	Methodology	Key findings
Casey et al[71]	59 GISTs (multi-institutional) + blood/saliva	SDHC promoter	Bisulfite sequencing	Epimutation found in approximately 94% of SDHx-WT cases, including Carney triad; mosaicism in peripheral tissues supports post-zygotic origin
Janeway et al[74]	Pediatric and WT GIST (approximately 100)	SDH subunits (SDHB, SDHC epimutations)	IHC + genetic/epigenetic testing	Established SDH-deficient GIST in children/WT adults; SDHB loss by IHC plus SDHC methylation testing defines subset
Haller et al[75]	Carney triad GISTs	SDHC promoter	Methylation assays	Recurrent SDHC hypermethylation identified as defining event in Carney triad, absent in Carney-Stratakis
Angelini et al[76]	63 tumors (KIT/PDGFRA-mutant vs SDH-deficient)	Genome-wide	450K arrays	C promoter hypermethylation represents a characteristic alteration in Carney triad but is not detected in Carney-Stratakis
Killian et al[70]	SDH-deficient vs syndromic GIST	Genome-wide	450K arrays	SDH-deficient GISTs characterized by a hypermethylator profile, with succinate accumulation blocking TET enzyme activity
Miettinen et al[72]	66/756 gastric GIST SDH-deficient	SDH status	IHC + molecular	Defined clinicopathologic spectrum of SDH-deficient GIST; IHC loss of SDHB as front-line marker
Saito et al[77]	35 GISTs	CpG island panel (p15, p16, p73, MGMT, hMLH1, MINT1/2/31)	MSP	94% tumors showed aberrant methylation; proposed CIMP-like category in GIST
Giger et al[78]	Plasma/tissue paired samples	SEPT9 (plasma methylation)	ddPCR	Circulating methylated SEPT9 showed feasibility as a liquid biopsy biomarker (AUC: 0.74-0.79)

GIST: Gastrointestinal stromal tumors; WT: Wild-type; SDH: Succinate dehydrogenase; SDHB: Succinate dehydrogenase subunit B; MGMT: O-6-methylguanine-DNA methyltransferase; IHC: Immunohistochemistry; MSP: Methylation-specific polymerase chain reaction; ddPCR: Droplet digital polymerase chain reaction; TET: Ten-eleven translocation; AUC: Area under the curve; CIMP: CpG island methylator phenotype.