A gastrointestinal stromal tumor (GIST) is a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. This type of tumor is thought to grow from specialized cells found in the gastrointestinal tract called interstitial cells of Cajal (ICCs) or precursors to these cells. Affected individuals can develop one or more tumors. GISTs are usually found in adults between ages 40 and 70; rarely, children and young adults develop this type of tumor.

Small tumors may cause no signs or symptoms. However, some people with GISTs may experience pain or swelling in the belly area (abdomen), nausea, vomiting, loss of appetite, or weight loss. Sometimes, tumors cause bleeding into the gastrointestinal tract, which may lead to low red blood cell counts (anemia) and, consequently, weakness and tiredness. Bleeding into the intestines may cause black and tarry stools, and bleeding into the throat or stomach may cause vomiting of blood.

Affected individuals with no family history of GIST typically have only one tumor (called a sporadic GIST). People with a family history of GISTs (called familial GISTs) often have multiple tumors and additional signs or symptoms, including noncancerous overgrowth (hyperplasia) of other cells in the gastrointestinal tract and patches of dark skin on various areas of the body. Some affected individuals have a skin condition called urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis), which is characterized by raised patches of brownish skin that sting or itch when touched.

A rare form of GIST, called succinate dehydrogenase (SDH)-deficient GIST, tends to occur in childhood or young adulthood and affects females more commonly than males. In this form, tumors are almost always in the stomach. Individuals with an SDH-deficient GIST have a high risk of developing other types of tumors, particularly noncancerous tumors in the nervous system called paragangliomas and noncancerous lung tumors called pulmonary chondromas. When GISTs occur in combination with paragangliomas, the condition is known as Carney-Stratakis syndrome; the combination of GISTs, paragangliomas, and pulmonary chondromas is known as Carney triad; and the combination of GISTs and pulmonary chondroma is known as incomplete Carney triad.

Approximately 5,000 new cases of GIST are diagnosed in the United States each year. SDH-deficient GIST accounts for about 5 to 7 percent of cases. However, GISTs may be more common than the estimate because small tumors may remain undiagnosed.

Genetic changes in one of several genes are involved in the formation of GISTs. About 80 percent of cases are associated with a mutation in the KIT gene, and about 10 percent of cases are associated with a mutation in the PDGFRA gene. Mutations in the KIT and PDGFRA genes are associated with both familial and sporadic GISTs. Less than 10 percent of cases are SDH-deficient GISTs, which are associated with mutations or other changes in the SDHA, SDHB, SDHC, or SDHD gene. SDH-deficient GIST can be familial or sporadic. A small number of people with a GIST have mutations in other genes.

The KIT and PDGFRA genes provide instructions for making receptor proteins that are found in the cell membrane of certain cell types. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. When a ligand attaches (binds), the KIT or PDGFRA receptor protein is turned on (activated), which leads to activation of a series of proteins in multiple signaling pathways. These signaling pathways control many important cellular processes, such as cell growth and division (proliferation) and survival.

Mutations in the KIT and PDGFRA genes lead to proteins that no longer require ligand binding to be activated. As a result, the proteins and the signaling pathways are constantly turned on (constitutively activated), which increases the proliferation and survival of cells and leads to the formation of tumors.

The SDHA, SDHB, SDHC, and SDHD genes provide instructions for making proteins that come together to form the succinate dehydrogenase (SDH) enzyme. The SDH enzyme is involved in cellular pathways that are critical for converting the energy from food into a form that cells can use. Specifically, the SDH enzyme converts a compound called succinate to another compound called fumarate. Succinate acts as an oxygen sensor in the cell and can help turn on specific pathways that stimulate cells to grow in a low-oxygen environment (hypoxia). 

Genetic Testing Information

• Genetic Testing Registry: Gastrointestinal stromal tumor

Genetic and Rare Diseases Information Center

• Gastrointestinal stromal tumor

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• GASTROINTESTINAL STROMAL TUMOR; GIST

Scientific Articles on PubMed

• PubMed

• Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, Besmer P, Antonescu CR. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008 Oct;47(10):853-9. doi: 10.1002/gcc.20589. Citation on PubMed or Free article on PubMed Central
• Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003 Jan 31;299(5607):708-10. doi: 10.1126/science.1079666. Epub 2003 Jan 9. Citation on PubMed
• Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998 Jan 23;279(5350):577-80. doi: 10.1126/science.279.5350.577. Citation on PubMed
• Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, Kitamura Y. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003 Sep;125(3):660-7. doi: 10.1016/s0016-5085(03)01046-1. Citation on PubMed
• Isozaki K, Terris B, Belghiti J, Schiffmann S, Hirota S, Vanderwinden JM. Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am J Pathol. 2000 Nov;157(5):1581-5. doi: 10.1016/S0002-9440(10)64795-5. Citation on PubMed or Free article on PubMed Central
• Oudijk L, Gaal J, Korpershoek E, van Nederveen FH, Kelly L, Schiavon G, Verweij J, Mathijssen RH, den Bakker MA, Oldenburg RA, van Loon RL, O'Sullivan MJ, de Krijger RR, Dinjens WN. SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors. Mod Pathol. 2013 Mar;26(3):456-63. doi: 10.1038/modpathol.2012.186. Epub 2012 Nov 23. Citation on PubMed
• Roskoski R Jr. Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor. Biochem Biophys Res Commun. 2005 Nov 11;337(1):1-13. doi: 10.1016/j.bbrc.2005.08.055. Citation on PubMed
• Wagner AJ, Remillard SP, Zhang YX, Doyle LA, George S, Hornick JL. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013 Feb;26(2):289-94. doi: 10.1038/modpathol.2012.153. Epub 2012 Sep 7. Citation on PubMed