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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Inactivating mutations targeting the chfr mitotic checkpoint gene in human lung cancer
George Mariatos1, John Bothos, Panayotis Zacharatos
1Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, University of Athens, Athens, Greece 11527.
Abstract:
A hallmark of cancer is inactivation of cell cycle checkpoints. However, very few mutations targeting mitotic checkpoint genes have been described, and in those instances, a wild-type copy of the gene was retained. chfr is a mitotic checkpoint gene that functions in early prophase delaying chromosome condensation in response to microtubule poisons. In a panel of 53 lung carcinomas for which matched normal tissue was available, we identified three missense mutations in the chfr gene, at least one of which was associated with loss of heterozygosity. In tissue culture checkpoint assays, the tumor-associated missense mutants had reduced activity or were inactive. Together with recent data suggesting that the chfr gene is frequently silenced in various tumors because of methylation of its promoter, these findings suggest that chfr is inactivated by multiple mechanisms in human cancer.
Insights
The CHFR gene, a mitotic checkpoint, is inactivated in human lung cancers through mutations and promoter methylation, disrupting cell cycle control.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer is characterized by the inactivation of cell cycle checkpoints.
- Mitotic checkpoint genes are rarely mutated in cancer, and if so, a functional copy is usually retained.
- The CHFR gene acts as a mitotic checkpoint, delaying chromosome condensation when cells are exposed to microtubule poisons.
Purpose of the Study:
- To investigate the role of the CHFR gene in lung carcinogenesis.
- To identify mutations in the CHFR gene in lung tumors.
- To assess the functional impact of identified CHFR mutations on mitotic checkpoint activity.
Main Methods:
- Analysis of CHFR gene mutations in 53 lung carcinoma samples with matched normal tissue.
- Loss of heterozygosity analysis for the CHFR gene.
- In vitro checkpoint assays using tumor-associated CHFR missense mutants.
Main Results:
- Three missense mutations in the CHFR gene were identified in lung carcinomas.
- At least one mutation was associated with loss of heterozygosity.
- Tumor-associated CHFR mutants exhibited reduced or absent checkpoint activity in cell culture assays.
Conclusions:
- The CHFR gene is inactivated by multiple mechanisms in human cancer, including mutations and promoter methylation.
- CHFR inactivation contributes to the loss of cell cycle checkpoint control in lung cancer.
- These findings highlight CHFR as a potential tumor suppressor gene in lung carcinogenesis.
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