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KIT mutations are common in testicular seminomas.
Kathleen Kemmer1, Christopher L Corless, Jonathan A Fletcher
1Division of Hematology and Oncology, Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
The American Journal of Pathology
|December 26, 2003
Summary
Activating KIT mutations are found in 25.9% of seminomas, driving tumor growth. These mutations, common in other cancers, were absent in non-seminomatous germ cell tumors, suggesting a specific role in seminoma development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KIT tyrosine kinase is crucial for germ cell development.
- Activating KIT mutations are implicated in gastrointestinal stromal tumors and mastocytosis.
- KIT expression is prevalent in seminomas.
Purpose of the Study:
- To investigate the frequency and types of KIT mutations in seminomas and other germ cell tumors.
- To assess the functional impact of identified KIT mutations.
- To determine the role of KIT mutations in tumorigenesis.
Main Methods:
- Genomic DNA analysis of 54 testicular seminomas, 1 ovarian dysgerminoma, and 37 non-seminomatous germ cell tumors (NSGCT).
- Transient transfection assays to evaluate mutant KIT protein phosphorylation and activation.
- Assessment of KIT-associated signaling pathways, including PI3K association.
- Testing sensitivity of mutant KIT isoforms to imatinib mesylate.
Main Results:
- Fourteen seminomas (25.9%) harbored exon 17 point mutations in KIT, including D816V, D816H, Y823D, Y823C, N822K, and T801I.
- No KIT mutations were detected in the ovarian dysgerminoma or NSGCTs.
- Mutant KIT isoforms D816V, D816H, Y823D, and N822K showed ligand-independent phosphorylation.
- D816V and D816H mutants were resistant to imatinib, while N822K and Y823D were sensitive.
- KIT activation markers correlated with genomic KIT mutations in seminomas.
Conclusions:
- Activating KIT mutations are present in a significant subset of seminomas.
- These mutations likely contribute to seminoma tumorigenesis.
- KIT mutations do not appear to play a role in NSGCT development.