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The p19INK4D cyclin dependent kinase inhibitor gene is altered in osteosarcoma
1Department of Medicine, UCLA School of Medicine, Cedars-Sinai Research Institute, Los Angeles, California 90048, USA.
Abstract:
Inhibition of cyclin dependent kinases (CDK) by cyclin dependent kinase inhibitors (CDKI) blocks cell cycle progression and inhibits cellular proliferation. The archetypical member of the INK4 CDKI family, p16INK4A (also called CDKN2), is a tumor suppressor frequently deleted or mutated in certain neoplasms and many cell lines. Because p19INK4D has strong structural and functional similarity to p16INK4A, we have assessed its role as a tumor suppressor. This was accomplished by screening the p19INK4D coding region for mutations, deletions and rearrangements in sarcomas and non-small cell lung cancers. Alterations of the p19INK4D gene were found in samples from five of 67 (7%) patients with osteosarcomas and none were found in other types of sarcomas or in lung cancers. Five osteosarcoma samples had Southern blot patterns consistent with gene rearrangement. These samples included a primary and recurrent osteosarcoma from the same patient; both with the same rearrangement. Four samples had SSCP patterns consistent with sequence alterations, sequencing determined that three were due to silent base changes and apparently polymorphisms. Sequencing the fourth shifted band revealed a one base insertion causing a frameshift beginning with codon 27. In summary, these studies found alterations affecting the p19INK4D gene in a small but significant number of osteosarcomas. Presumably, abnormalities of this gene contribute to the development of cancer of bone cells.
Insights
Alterations in the p19INK4D gene were identified in osteosarcomas, suggesting its role as a tumor suppressor in bone cancer development. These findings highlight potential new avenues for cancer research.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cyclin-dependent kinases (CDKs) regulate the cell cycle; their inhibition by cyclin-dependent kinase inhibitors (CDKIs) halts proliferation.
- p16INK4A, a key CDKI, functions as a tumor suppressor and is often altered in neoplasms.
- p19INK4D shares structural and functional similarities with p16INK4A, prompting investigation into its tumor suppressor role.
Purpose of the Study:
- To evaluate the role of p19INK4D as a tumor suppressor.
- To screen for mutations, deletions, and rearrangements in the p19INK4D gene in sarcomas and non-small cell lung cancers.
Main Methods:
- Screening of the p19INK4D coding region for genetic alterations.
- Utilizing Southern blot analysis to detect gene rearrangements.
- Employing Single-Strand Conformation Polymorphism (SSCP) and sequencing to identify sequence alterations.
Main Results:
- Alterations in the p19INK4D gene were detected in 7% of osteosarcoma samples (5 out of 67).
- Gene rearrangements were observed in five osteosarcoma samples, including a primary and recurrent tumor pair.
- Sequence analysis revealed silent base changes (polymorphisms) in three samples and a frameshift mutation due to a one-base insertion in another.
Conclusions:
- Genetic alterations affecting the p19INK4D gene occur in a subset of osteosarcomas.
- These abnormalities are presumed to contribute to the pathogenesis of bone cancers.
- p19INK4D warrants further investigation as a potential tumor suppressor in osteosarcoma.