Gastrointestinal Stromal Tumor (GIST)

Most gastrointestinal stromal tumors (GISTs) are caused primarily by gain-of-function mutations in exon 11 of the c-kit proto-oncogene, which is located on chromosome arm 4q11-12.1 The KIT gene codes for KIT transmembrane tyrosine kinase proteins.1 Gain-of-function mutations enhance the activity of these proteins.2 GIST gain-of-function mutations are classified as being of the in-frame type where base pairs are substituted with mutated versions. In-frame mutations allow the transcription and translation process of protein synthesis, in which the DNA sequence is read, to continue because no reading frame shift occurs despite the mutation. Therefore, only a few amino acids are changed during synthesis, resulting in c-kit expression and the activation of abnormal, but functional, tyrosine kinase proteins.1,3 

Normally, stem cell factor, also known as mast cell growth factor or Steel factor, is the ligand that activates tyrosine kinase proteins on attachment to the c-kit extracellular domain. When the protein kinases become activated, a phosphate group is added, and phosphorylation in turn activates the intracellular signal transduction cascade pathway that ultimately is responsible for cellular proliferation.1

In most cases of GIST, the KIT tyrosine kinase proteins are ligand-independent, which means that binding of the stem cell factor ligand is not required to activate them. Therefore, they are constantly activated, and the resulting continuous signal transduction favors cell growth and division over apoptosis. Ultimately, tumors form that originate within the interstitial cells of Cajal (ICC) or the pacemaker cells innervated by the autonomic nervous system to maintain gut peristalsis.1,4  

The expression of KIT protein, also known as CD117, is detected through immunohistochemical staining and molecular analysis, which are the gold standard for a diagnosis of GIST. Other protein markers, such as DOG1 and PKC0, are also expressed in GISTs, and clinicians may use these markers in the diagnosis of CD117-negative GISTs.5 

Approximately 80% of GISTs have a mutation in the KIT gene, and 5% to 10% of GISTs have a mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene.6 The platelet-derived growth factor receptor alpha protein encoded by the PDGFRA gene belongs to the same family of tyrosine kinase proteins as the KIT tyrosine kinase protein, with a similar function of signal transduction via phosphorylation. The ligand normally responsible for the activation of PDGFRA protein is platelet-derived growth factor, but in the case of a PDGFRA mutation, the protein is ligand-independent and constantly activated. Like those activated by the KIT protein, the signal transduction pathways activated by PDGFRA protein promote abnormal cell proliferation and survival, leading to tumor formation.7 PDGFRA mutations lead to tumor development primarily in the stomach. Most of the time, these mutations are sporadic somatic mutations that are acquired during an individual’s lifetime, but occasionally PDGFRA mutations may be inherited, resulting in familial GISTs.7 

Familial GISTs, which comprise a small minority of GISTs, are characterized by germline mutations in the KIT or PDGFRA gene and associated with several comorbidities: irritable bowel syndrome (IBS), diverticular disease, cutaneous hyperpigmentation, and dysphagia.1 In 90% of individuals with these germline mutations, GISTs may develop by the time they reach 70 years of age. In individuals who inherit autosomal dominant KIT mutations, multiple GISTs may develop at an earlier age. Familial GISTs are not associated with shortened survival; therefore, the outcome is more favorable than with sporadic GISTs.1

Unlike the 80% of GIST mutations that occur in the KIT gene and the 5% to 10% that occur in the PDGFRA gene, the remaining 5% to 10% are termed wild-type GISTs. Wild-type GISTs are subdivided into succinate dehydrogenase (SDH)-deficient and non-SDH-deficient categories.8 When a wild-type GIST is suspected, intensive genetic analysis and careful, long-term monitoring are warranted. 

GISTs in patients with Carney triad or Carney-Stratakis syndrome belong to the SDH-deficient group of GISTs, which are caused by subunit A, B, C, or D mutations of the SDH gene.9 Carney triad manifests with a combination of gastric GISTs, pulmonary chondromas, and paragangliomas.1 Carney-Stratakis syndrome is characterized by the development of gastric GISTs and paragangliomas.1 Both syndromes affect primarily young women, in whom GISTs with epithelioid tumor cells occur in the antrum of the stomach. In both Carney triad and Carney-Stratakis syndrome, GIST metastasis to the lymph nodes is common.8 SDH-deficient GISTs are familial or syndromic in 90% of cases.9 

The non-SDH-deficient group consists of GISTs caused by a mutation in the neurofibromatosis type 1 (NF1) gene and GISTs with mutations identified in the BRAF, KRAS, PIK3CA, and ETV6-NTRK3 fusion genes. Neurofibromatosis type 1 is manifested by wild-type, multicentric GISTs that contain spindle-shaped tumor cells and are located primarily in the small intestine.1,8 BRAF mutations occur in roughly 7% of the subset of wild-type intestinal GISTs, which affect predominantly the small intestine and carry a high-risk of malignancy.6,10 


  1. Choti MA. Gastrointestinal stromal tumors (GISTs): etiology. Medscape. Updated March 17, 2021. Accessed June 25, 2021.
  2. Medical definition of gain-of-function mutation. MedicineNet. Accessed June 25, 2021.
  3. In-frame mutation. Muscular Dystrophy UK. Accessed June 25, 2021.
  4. Min KW, Leabu M. Interstitial cells of Cajal (ICC) and gastrointestinal stromal tumor (GIST): facts, speculations, and myths. J Cell Mol Med. 2006;10(4):995-1013. doi:10.1111/j.1582-4934.2006.tb00541.x
  5. Wu C-E, Tzen C-Y, Wang S-Y, Yeh C-N. Clinical diagnosis of gastrointestinal stromal tumor (GIST): from the molecular genetic point of view. Cancers (Basel). 2019;11(5):679. doi:10.3390/cancers11050679
  6. Gastrointestinal stromal tumors (GISTs), c-KIT mutation analysis with reflex to PDGFRA mutation analysis. Labcorp. Accessed June 25, 2021.
  7. PDGFRA gene. MedlinePlus. Updated August 18, 2020. Accessed June 25, 2021. 
  8. Wada R, Arai H, Kure S, Peng W-X, Naito Z. “Wild type” GIST: clinicopathological features and clinical practice. Pathol Int. 2016; 66(8):431-437. doi:10.1111/pin.12431
  9. Mei L, Smith SC, Faber AC, et al. Gastrointestinal stromal tumors: the GIST of precision medicine. Trends in Cancer. 2018; 4(1):74-91. doi:10.1016/j.trecan.2017.11.006
  10. Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008; 47(10):853-859. doi:10.1002/gcc.20589 

Article reviewed by Kyle Habet, MD, on July 1, 2021.