Table 11.

GIST mutations’ clinical course and management. High Risk is in bold and underlined.

Gene	Alteration	Clinical Features	Recommended Targeted Therapy (Potential Superior Therapy)
KIT	Exon 11 W557_558del	Classic GISTs (V559 and V560) W557 more aggressive in the stomach Half W557 non-gastric, avg. 8 cm	Imatinib standard dose
	Exon 9 A502_Y503dup	Locally aggressive, spindle cell Non-gastric, younger, >5 cm	Potential adjuvant therapy Imatinib high dose Sunitinib
	Exons 13, 14, and 17	Secondary mutations resistant to imatinib/sunitinib	Sunitinib and ponatinib
PDGFR	Exon 18 D842V	PDGFRA alteration, mostly gastric Favorable outcomes Resistance to imatinib and sunitinib	Avapritinib No adjuvant therapy recommended Neoadjuvant avapritinib may be considered
	Exons 13–15 Codons 596–719	Resistance to avapritinib	Imatinib standard dose (Trametinib)
	Exon 12 Codons 555–589	Primary non-gastric GISTs, rare	Imatinib standard dose
SDHA-D	Hypermethylation, truncation, frameshift, Splice site alterations	Carney triad syndrome (often SDHC) Multifocal gastric GISTs, pulmonary chondroma paraganglioma Younger with female > male Carney–Stratakis syndrome Germline, gastric GISTs, and paraganglioma Paternal inheritance (SDHD) Potential lymph node metastasis	Avoid TKIs Personalized treatment
BRAF	V600E	Resistant to standard GIST guideline TKIs	Off-label indication of BRAF and BRAF–MEK inhibitors
NF1	Truncation Frameshift	Germline Most GIST in small bowel	Avoid adjuvant therapy Personalized treatment
NTRK1,2,3	Fusions	Resistant to standard GIST guideline TKIs	NTRK inhibitors (Larotrectinib and entrectinib)