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Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors
S Hirota1, K Isozaki, Y Moriyama
1Department of Pathology, Osaka University Medical School, Yamada-oka 2-2, Suita 565, Japan.
Abstract:
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.
Insights
Gastrointestinal stromal tumors (GISTs) harbor mutations in the KIT gene, leading to its constant activation. These mutations suggest a role in GIST development and may point to interstitial cells of Cajal as the cellular origin.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract.
- The molecular origins and cellular source of GISTs remain largely unknown.
Purpose of the Study:
- To investigate the molecular alterations in GISTs.
- To identify the cellular origin of GISTs.
Main Methods:
- Sequencing of c-kit complementary DNA from GIST samples.
- Assessing KIT protein activation.
- Transfection of mutant c-kit into murine lymphoid cells (Ba/F3).
Main Results:
- Mutations were identified in the c-kit gene in GISTs.
- Mutant KIT proteins exhibited constitutive activation.
- Transfection of mutant c-kit induced malignant transformation in Ba/F3 cells.
Conclusions:
- Mutations in KIT are implicated in GIST development.
- GISTs may originate from interstitial cells of Cajal (ICCs) due to shared KIT expression and SCF-KIT pathway dependence.