Gastrointestinal stromal tumor causes

Gastrointestinal stromal tumor Microchapters
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Epidemiology and Demographics
Risk Factors
Screening
Differentiating Gastrointestinal stromal tumor from other Diseases
Natural History, Complications and Prognosis
Diagnosis
Staging
History and Symptoms
Physical Examination
Laboratory Findings
Chest X Ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Gastrointestinal stromal tumor causes On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Gastrointestinal stromal tumor causes All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Gastrointestinal stromal tumor causes
CDC on Gastrointestinal stromal tumor causes
Gastrointestinal stromal tumor causes in the news
Blogs on Gastrointestinal stromal tumor causes
Directions to Hospitals Treating Gastrointestinal stromal tumor
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: 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.

• 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)