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Deletion of p16 and p15 genes in brain tumors
J Jen1, J W Harper, S H Bigner
1Johns Hopkins Oncology Center, Baltimore, Maryland 21231.
Abstract:
We have used molecular genetic methods to examine the status of cell cycle-inhibitory genes in human brain tumors. We found that p16 and a neighboring gene, p15, were often homozygously deleted in glioblastoma multiformes but not in medulloblastomas or ependymomas. The deletions occurred in both primary tumors and their derived xenografts, but no intragenic mutations in either of the two genes were found. The p15 gene was expressed in a more widespread pattern in normal tissues than p16, but the products of both genes had similar capacities to bind to cyclin D-dependent kinases 4 and 6. These data suggest that the target of deletion in glioblastoma multiforme includes both p15 and p16 genes. The reason that homozygous deletions, rather than intragenic mutations, are so common in these tumors may be that deletion is a more efficient mechanism for simultaneous inactivation of both genes.
Insights
Glioblastoma multiforme frequently shows homozygous deletions of cell cycle genes p15 and p16. This contrasts with other brain tumors, suggesting deletion is key for inactivating these tumor suppressor genes.
Area of Science:
- Molecular genetics
- Oncology
- Cancer biology
Background:
- Cell cycle regulation is crucial for preventing uncontrolled cell proliferation in cancer.
- Tumor suppressor genes, such as p15 and p16, play a vital role in cell cycle inhibition.
- Alterations in these genes are implicated in the development of various human cancers, including brain tumors.
Purpose of the Study:
- To investigate the status of cell cycle-inhibitory genes, specifically p15 and p16, in human brain tumors.
- To determine if homozygous deletions or intragenic mutations are prevalent in glioblastoma multiforme, medulloblastoma, and ependymoma.
- To understand the differential expression and functional roles of p15 and p16 in normal tissues and tumors.
Main Methods:
- Molecular genetic analysis of human brain tumor samples and derived xenografts.
- Analysis of gene deletions and intragenic mutations using genetic methods.
- Gene expression profiling in normal tissues.
- In vitro studies assessing the binding capacity of p15 and p16 gene products to cyclin-dependent kinases 4 and 6.
Main Results:
- Homozygous deletions of both p15 and p16 genes were frequently observed in glioblastoma multiforme.
- These deletions were absent in medulloblastomas and ependymomas.
- No intragenic mutations were detected in p15 or p16 in the analyzed tumors.
- Both p15 and p16 gene products demonstrated similar abilities to bind to cyclin D-dependent kinases 4 and 6.
Conclusions:
- The study identifies homozygous deletion of p15 and p16 as a common event in glioblastoma multiforme.
- These findings suggest that simultaneous inactivation of both p15 and p16 through deletion is a critical mechanism in glioblastoma development.
- Deletion appears to be a more efficient mechanism than intragenic mutation for inactivating both tumor suppressor genes concurrently in these brain tumors.