Gastrointestinal stromal tumor causes: Difference between revisions
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Common causes of gastrointestinal stromal tumor include mutation in c-Kit gene and PDGFRA gene. | Common causes of gastrointestinal stromal tumor include mutation in c-Kit gene and PDGFRA gene. | ||
[[Genes]] involved in the [[pathogenesis]] of gastrointestinal stromal tumors include [[mutations]] in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. In some rare 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]]. The majority of GISTs are sporadic in origin. <ref name="pmid14645423">{{cite journal |vauthors=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 |title=Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor |journal=J. Clin. Oncol. |volume=21 |issue=23 |pages=4342–9 |year=2003 |pmid=14645423 |doi=10.1200/JCO.2003.04.190 |url=}}</ref><ref name="pmid9438854">{{cite journal |vauthors=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 |title=Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors |journal=Science |volume=279 |issue=5350 |pages=577–80 |year=1998 |pmid=9438854 |doi= |url=}}</ref><ref name="DuensingMedeiros2004">{{cite journal|last1=Duensing|first1=Anette|last2=Medeiros|first2=Fabiola|last3=McConarty|first3=Bryna|last4=Joseph|first4=Nora E|last5=Panigrahy|first5=Dipak|last6=Singer|first6=Samuel|last7=Fletcher|first7=Christopher DM|last8=Demetri|first8=George D|last9=Fletcher|first9=Jonathan A|title=Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs)|journal=Oncogene|volume=23|issue=22|year=2004|pages=3999–4006|issn=0950-9232|doi=10.1038/sj.onc.1207525}}</ref><ref name="LuxRubin2000">{{cite journal|last1=Lux|first1=Marcia L.|last2=Rubin|first2=Brian P.|last3=Biase|first3=Tara L.|last4=Chen|first4=Chang-Jie|last5=Maclure|first5=Timothy|last6=Demetri|first6=George|last7=Xiao|first7=Sheng|last8=Singer|first8=Samuel|last9=Fletcher|first9=Christopher D.M.|last10=Fletcher|first10=Jonathan A.|title=KIT Extracellular and Kinase Domain Mutations in Gastrointestinal Stromal Tumors|journal=The American Journal of Pathology|volume=156|issue=3|year=2000|pages=791–795|issn=00029440|doi=10.1016/S0002-9440(10)64946-2}}</ref> | |||
*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 [[Exon|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 4|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]]. | |||
{{familytree/start |summary=Sample 1}} | |||
{{familytree | | | | | | | | | | | | | A01 |A01=Gastrointestinal stromal tumors}} | |||
{{familytree | | | | | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| }} | |||
{{familytree | | | | | | C01 | | | | | C02 | | | | | C03 |C01=KIT gene mutation|C02=PDGFRA mutation|C03=Wild type (absence of KIT/PDGFRA)}} | |||
{{familytree | | |,|-|-|-|^|-|-|-|.| | | | | | | | | |!| |}} | |||
{{familytree | | D01 | | | | | | D02 | | | | | | | | D03 |D01=Exon 9,13 & 17|D02=Exon 11|D03=Mutant succinate dehydrogenase}} | |||
{{familytree | | |!| | | | | | | |!| | | | | | | | | |!| |}} | |||
{{familytree | | E01 | | | | | | E02 | | | | | | | | E03 |E01=Uncontrolled KIT signalling|E02=KIT receptor mutation|E03=Dysfunction of electron transport mitochondria}} | |||
{{familytree | | | | | | | | | | | | | | | | | | | | |!| |}} | |||
{{familytree | | | | | | | | | | | | | | | | | | | | F01 |F01=Defective oxidative phosphorylation}} | |||
{{familytree | | | | | | | | | | | | | | | | | | | | |!| |}} | |||
{{familytree | | | | | | | | | | | | | | | | | | | | G01 |G01=Abnormal stabilization of HIF}} | |||
{{familytree/end}} | |||
==References== | ==References== | ||
Revision as of 13:19, 15 December 2017
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Gastrointestinal stromal tumor Microchapters |
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Differentiating Gastrointestinal stromal tumor from other Diseases |
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Gastrointestinal stromal tumor causes On the Web |
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American Roentgen Ray Society Images of Gastrointestinal stromal tumor causes |
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Directions to Hospitals Treating Gastrointestinal stromal tumor |
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Risk calculators and risk factors for Gastrointestinal stromal tumor causes |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]
Overview
There are no established causes for gastrointestinal stromal tumor.
Causes
Most GISTs are sporadic. Less than 5% occur as part of hereditary, familial, or idiopathic multitumor syndromes.
Common causes of gastrointestinal stromal tumor include mutation in c-Kit gene and PDGFRA gene. Genes involved in the pathogenesis of gastrointestinal stromal tumors include mutations in c-Kit gene and PDGFRA (platelet derived growth factor receptor-alpha) gene. In some rare 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. The majority of GISTs are sporadic in origin. [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 | |||||||||||||||||||||||||||||||||||||||||||||
| KIT gene mutation | PDGFRA mutation | Wild type (absence of KIT/PDGFRA) | |||||||||||||||||||||||||||||||||||||||||||
| Exon 9,13 & 17 | Exon 11 | Mutant succinate dehydrogenase | |||||||||||||||||||||||||||||||||||||||||||
| Uncontrolled KIT signalling | KIT receptor mutation | Dysfunction of electron transport mitochondria | |||||||||||||||||||||||||||||||||||||||||||
| Defective oxidative phosphorylation | |||||||||||||||||||||||||||||||||||||||||||||
| Abnormal stabilization of HIF | |||||||||||||||||||||||||||||||||||||||||||||
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.