Gastrointestinal stromal tumor causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Molecular genetics have drastically changed the understanding of gastrointestinal stromal tumors (GIST). Genetic mutations are considered the most identifiable cause of GIST. Around 95% of these mutations are sporadic with less than 5% occur as part of hereditary, familial, or idiopathic multi tumor syndromes. Common causes of gastrointestinal stromal tumor include mutation in c-Kit gene and PDGFRA gene. In other cases where the patient do not exhibit the typical mutation in c-Kit and PDGFRA , mutations in succinate dehydrogenase (SDH) have been reported. Rare genes involved include mutation in BRAF kinase, and protein kinase C.

Common causes of gastrointestinal stromal tumor include mutation in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. In other cases where the patient do not exhibit the typical c-Kit and PDGFRA mutation, mutation in succinate dehydrogenase (SDH) have been reported. Rare genes involved include BRAF kinase, and protein kinase C. Around 95% of these mutations are sporadic with less than 5% occur as part of hereditary, familial, or idiopathic multi tumor syndromes.^[1][2][3][4]

• The c-kit gene is a proto-oncogene and located on chromosome 4q11-12 (long (q) arm of chromosome 4 at position 12).
  • The c-kit gene encodes for KIT protein which is a transmembrane tyrosine kinase.
  • The KIT protein is located on the cell membrane of certain cell types.
  • Stem cell factor is the ligand that binds to KIT protein, which in turn leads to activation of KIT protein.
  • Upon activation, the KIT protein leads to activation of other intracellular proteins by a process known as phosphorylation (which involves adding oxygen and phosphorus at specific positions).
  • The activation of these intracellular proteins such as (MAP kinase and RAS) plays a vital role in multiple signaling pathways.
  • The signaling pathways stimulated by the KIT protein control many important cellular processes, such as cell growth and proliferation.
  • In addition, KIT protein signaling also has a role in the development of gastrointestinal tract cells known as interstitial cells of Cajal.
  • The most commonly observed mutation site in c-Kit gene involves exon 11 leading to a gain-of-function mutation. Less common sites include exons 9 and 13.
  • Gain of function mutation leads to overexpression and autophosphorylation of c-Kit that leads to inhibition of apoptosis and uncontrolled cell proliferation.
  • Almost 90-95% of patients with GIST have mutated c-Kit gene.
  • C-Kit (a tyrosine kinase growth factor receptor) is also the target of medical therapy in GIST; ST-571 (Imatinib; Glivec).
• About 10% cases of GIST are associated with PDGFRA gene.
  • The PDGFRA gene is located on chromosome 4q11-12 (long (q) arm of chromosome 4 at position 12).
  • The PDGFRA gene encodes for the protein; platelet-derived growth factor receptor alpha (PDGFRA), which belongs to a family of proteins known as receptor tyrosine kinases.
    • The platelet-derived growth factor is the ligand that binds to PDGFRA, which in turn activates the PDGFRA.
    • Upon activation, the PDGFRA leads to activation of other intracellular proteins by a process known as phosphorylation (same as c-Kit explained above).
    • The activation of these intracellular proteins such as (MAP kinase and RAS) plays a vital role in multiple signaling pathways.
    • The multiple signaling pathways stimulated by PDGFRA gene control many important cellular processes such as cell growth and proliferation.
  • The most commonly observed mutation site in PDGFRA gene involves exon 18.
  • As a result of mutation, the PDGFRA gene gets activated on its own and leads to inhibition of apoptosis and uncontrolled cell proliferation.

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