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Genetic alterations and protein expression of KIT and PDGFRA in serous ovarian carcinoma
1Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, Helsinki 00290, Finland.
Abstract:
KIT and PDGFRA are receptor tyrosine kinases that can be specifically inactivated by small-molecule tyrosine kinase inhibitors, notably imatinib mesylate. In ovarian carcinoma, expression of KIT and PDGFRA protein has been documented, but the frequency and the molecular background of expression are poorly known. We analysed the expression of KIT and PDGFRA by immunohistochemistry in 522 serous ovarian carcinomas, and mutations of KIT and PDGFRA by denaturing high-performance liquid chromatographyin 125 and 187 serous ovarian carcinomas, respectively. No mutations of KIT or PDGFRA were detected. KIT expression was detected in 12% of carcinomas: low expression in 10% and high expression in 2% of cases. Using normal serous epithelium as a reference, decreased PDGFRA expression was detected in 12% and increased expression in 13% of carcinomas. Both KIT and PDGFRA expression were associated with high tumour grade, high proliferation index and poor patient outcome. By fluorescence in situ hybridisation, no KIT amplification was found in carcinomas with high KIT expression, but two cases showed a relative gain of chromosome 4. In conclusion, no mutations of KIT or PDGFRA were found, but a subset of serous ovarian carcinoma showed overexpression of the proteins, which was associated with aggressive tumour characteristics.
Insights
No mutations were found in KIT or PDGFRA genes in ovarian cancer. However, some ovarian carcinomas overexpressed these proteins, correlating with aggressive tumor traits and poor patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KIT and PDGFRA are receptor tyrosine kinases targeted by tyrosine kinase inhibitors.
- Their expression and molecular basis in ovarian carcinoma are not well understood.
- Previous studies suggest their potential role in ovarian cancer.
Purpose of the Study:
- To investigate the frequency and molecular characteristics of KIT and PDGFRA expression in serous ovarian carcinomas.
- To determine if mutations in KIT or PDGFRA are present in these tumors.
- To assess the association between KIT/PDGFRA expression and clinicopathological features and patient outcomes.
Main Methods:
- Immunohistochemistry was used to analyze KIT and PDGFRA protein expression in 522 serous ovarian carcinomas.
- Denaturing high-performance liquid chromatography was employed to detect mutations in KIT (125 cases) and PDGFRA (187 cases).
- Fluorescence in situ hybridization was performed to investigate KIT gene amplification.
Main Results:
- No mutations in KIT or PDGFRA genes were detected in the analyzed ovarian carcinomas.
- KIT protein expression was observed in 12% of cases (10% low, 2% high).
- PDGFRA expression was altered in 12% (decreased) and 13% (increased) of carcinomas compared to normal tissue. KIT and PDGFRA overexpression correlated with high tumor grade, proliferation, and poor patient outcome. No KIT amplification was found, but two cases showed chromosome 4 gain.
Conclusions:
- KIT and PDGFRA mutations are not a feature of serous ovarian carcinoma.
- Overexpression of KIT and PDGFRA proteins occurs in a subset of these tumors.
- This overexpression is linked to aggressive tumor characteristics and unfavorable prognosis, suggesting potential therapeutic implications.
