Table 1.

Summary of rare mutations identified in wild-type GISTs, including data on the clinical course and treatment sensitivity

Wild-type GIST subtype	Primary molecular abnormality	Clinicopathological features	Potential therapies/clinical notes	References
SDH-deficient GISTs	Germinal mutations in SDHA/B/C/D or epimutation of the SDHC promoter; loss of SDHB expression	Age under 40 years, predominantly women, stomach, multiple tumors, lymph node metastases; often clinically indolent	Surgery; low sensitivity to imatinib; relatively good response to sunitinib/regorafenib; experimental therapies	[12, 44]
Carney triad	SDHC epimutation (promoter hypermethylation); previously proposed 1q deletion (SDHC)	Non-hereditary; almost exclusively women; SDH-deficient GISTs, pulmonary chondromas, paragangliomas; synchronous or metachronous components	Consider genetic testing; there may be phenotypic overlap with other syndromes	[73]
BRAF V600E-mutated GISTs	Activating BRAF mutation	Mainly the small intestine; spindle-shaped morphology; variable clinical course	Surgery; BRAF ± MEK inhibitors (e.g., dabrafenib + trametinib)	[74]
NF1-associated GISTs	NF1 LoF mutations → activation of the RAS/RAF/MAPK pathway	Heterogeneous group; often small intestine	No response to imatinib; surgical treatment; studies on MEK inhibitors	[75]
FGFR-activated GISTs	FGFR1 GOF mutations, FGFR1 fusions, FGF3/4/19 amplifications	Heterogeneous presentation; sometimes triple or quadruple WT GIST	Regorafenib (depending on the FGFR pathway); potential FGFR inhibitors	[66, 70]
GISTs with NTRK fusions	NTRK1/2/3 fusions (e.g., ETV6-NTRK3)	Rare; no characteristic phenotype	NTRK inhibitors (larotrectinib, entrectinib)	[66, 67]
KRAS-mutated GISTs	KRAS mutations (e.g., G12D, G13D)	Often aggressive course, resistance to TKIs	Lack of efficacy of imatinib; studies on KRAS inhibitors	[74]
GISTs with DNA damage response defects	Mutations in CHEK2, FANCA, and other DNA repair genes	Limited data	Potential PARP inhibitors (hypothesis)	[76]
Quadruple-negative GISTs	No KIT/PDGFRA mutations, no SDH deficiency, no RAS/RAF/MAPK alterations	Heterogeneous group with diverse features	NGS diagnostics crucial to identify mutations; targeted therapies based on the detected condition	[69, 72]

DDR DNA damage repair, FGFR fibroblast growth factor receptor, GIST gastrointestinal stromal tumors, GOF gain-of-function, LoF loss-of function, NGS next-generation sequencing, NTRK neurotrophic tyrosine receptor kinase, SDH succinate dehydrogenase, TKIs tyrosine kinase inhibitors