Mutations are unusual changes in the material (DNA) of a cell.¹ In GIST, specific mutations can cause a cell to become malignant and thus cause cancer. Mutational testing identifies these genetic errors (mutations) found in tumor cells and is traditionally done by determining the nucleotide sequence of a particular gene. Mutational analysis is especially important in GIST because most GISTs are defined by activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. Additionally, the response of GISTs to certain drug treatments may vary according to the mutation status.²

Ninety-five percent of GISTs test positively for KIT tyrosine kinase (CD117), which is the most specific marker for GIST in immunohistochemical testing.¹ However, it is important to note that KIT staining is not conclusive for KIT mutational status, as some tumors that stain weakly or not at all have been shown to harbor KIT mutations, while others that are positive for KIT may contain the wild-type form.³

KIT is a type III receptor tyrosine kinase that is normally activated by its ligand, stem-cell factor (SCF).³

KIT mutations are oncogenic and have been shown to activate downstream signaling pathways, including MAP kinase, STAT, and phosphatidylinositol 3 (PI3)-kinase/AKT.³

More than two-thirds of GISTs have KIT mutations at exon 11; the second most-common mutation, at exon 9, is seen in approximately 10% of patients. Mutations at exons 13 and 17 are rare and occur in less than 3% of patients.^3,4 (See figure below.)

Interestingly, up to 15% of GISTs contain wild-type KIT. Of these, nearly one-third have mutations in PDGFRA, a receptor tyrosine kinase with a structure similar to that of KIT and identical downstream effects.³

While exon 11 KIT mutations can be found in GISTs throughout the GI tract, KIT mutations at exon 9 are found primarily in the small intestine and colon, and GISTs with mutations in PDGFR most commonly arise in the stomach.³ (See table below.)