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Activating c-kit gene mutations in human germ cell tumors
Q Tian1, H F Frierson, G W Krystal
1Departments of Pathology, University of Virginia Health Sciences Center, Charlottesville, USA.
Abstract:
The c-kit gene encodes a tyrosine kinase receptor (KIT) that is required in normal spermatogenesis and is expressed in seminomas and dysgerminomas, a subset of human germ cell tumors (GCTs). To determine whether activating mutations of the c-kit gene occur in GCTs, primary tissue samples of 33 testicular and ovarian tumors were examined for mutations in the juxtamembrane and phosphotransferase domains by polymerase chain reaction amplification and DNA sequencing. A novel missense mutation (D816H) was found in the phosphotransferase domain in tumors of seminoma/dysgerminoma differentiation. The c-kit alleles in nonneoplastic tissues from these patients were wild type, suggesting that the mutant alleles were acquired and selected for during malignant transformation. In cell transfection experiments, the D816H mutant protein was a constitutively activated kinase and was constitutively phosphorylated on tyrosine residues. This is the first description of an activating c-kit mutation in GCTs and is evidence that the KIT signal transduction pathway is important in the pathogenesis of neoplasms with seminoma differentiation.
Insights
Activating mutations in the c-kit gene were discovered in human germ cell tumors (GCTs). This finding indicates the KIT signaling pathway is crucial for seminoma tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The c-kit gene encodes a tyrosine kinase receptor (KIT) vital for spermatogenesis.
- KIT is expressed in seminomas and dysgerminomas, a subset of human germ cell tumors (GCTs).
Purpose of the Study:
- To investigate the presence of activating mutations in the c-kit gene within GCTs.
- To understand the role of the KIT signaling pathway in the pathogenesis of GCTs.
Main Methods:
- Analysis of primary tissue samples from 33 testicular and ovarian tumors.
- Polymerase chain reaction amplification and DNA sequencing to detect mutations in c-kit domains.
- Cell transfection experiments to assess the functional impact of identified mutations.
Main Results:
- A novel missense mutation (D816H) in the c-kit phosphotransferase domain was identified in seminoma/dysgerminoma tumors.
- The D816H mutant KIT protein demonstrated constitutive kinase activation and phosphorylation.
- Wild-type c-kit alleles were observed in nonneoplastic tissues, suggesting acquired mutations during tumorigenesis.
Conclusions:
- This study reports the first activating c-kit mutation found in GCTs.
- The KIT signal transduction pathway plays a significant role in the pathogenesis of neoplasms exhibiting seminoma differentiation.