Gastrointestinal stromal tumor causes
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]
Overview
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.
Causes
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.
| Gastrointestinal stromal tumors | |||||||||||||||||||||||||||||||||||||||||||||||
| Uncontrolled cell proliferation can be from | |||||||||||||||||||||||||||||||||||||||||||||||
| KIT gene mutation | PDGFRA mutation | Wild type (absence of KIT/PDGFRA mutation) | |||||||||||||||||||||||||||||||||||||||||||||
| Exon 9,13 & 17 | Exon 11 | Exon 18 | Mutant succinate dehydrogenase | ||||||||||||||||||||||||||||||||||||||||||||
| Uncontrolled KIT signalling | KIT receptor mutation & uncontrolled activation | Uncontrolled activation | Dysfunction of electron transport mitochondria | ||||||||||||||||||||||||||||||||||||||||||||
| Defective oxidative phosphorylation | |||||||||||||||||||||||||||||||||||||||||||||||
| Abnormal stabilization of HIF transcription factor (Hypoxia-inducible factor-1) | |||||||||||||||||||||||||||||||||||||||||||||||
References
- ↑ Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003). "Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor". J. Clin. Oncol. 21 (23): 4342–9. doi:10.1200/JCO.2003.04.190. PMID 14645423.
- ↑ 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 (1998). "Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors". Science. 279 (5350): 577–80. PMID 9438854.
- ↑ Duensing, Anette; Medeiros, Fabiola; McConarty, Bryna; Joseph, Nora E; Panigrahy, Dipak; Singer, Samuel; Fletcher, Christopher DM; Demetri, George D; Fletcher, Jonathan A (2004). "Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs)". Oncogene. 23 (22): 3999–4006. doi:10.1038/sj.onc.1207525. ISSN 0950-9232.
- ↑ Lux, Marcia L.; Rubin, Brian P.; Biase, Tara L.; Chen, Chang-Jie; Maclure, Timothy; Demetri, George; Xiao, Sheng; Singer, Samuel; Fletcher, Christopher D.M.; Fletcher, Jonathan A. (2000). "KIT Extracellular and Kinase Domain Mutations in Gastrointestinal Stromal Tumors". The American Journal of Pathology. 156 (3): 791–795. doi:10.1016/S0002-9440(10)64946-2. ISSN 0002-9440.