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Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers

T Nobori1, K Miura, D J Wu

  • 1Department of Medicine, University of California, San Diego, La Jolla 92093-0663.

Nature
|April 21, 1994
PubMed

Insights

Cytogenetic abnormalities in chromosome 9p21 are linked to various cancers. Researchers identified the CDK4-inhibitor gene as frequently deleted or rearranged in these cancers, suggesting its role in tumor suppression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cytogenetic abnormalities involving chromosome 9p21 are frequently observed in several human malignancies, including melanoma, glioma, lung cancer, and leukemia.
  • The specific region on 9p21 most commonly deleted in these cancers has not been precisely defined.
  • Understanding the genetic alterations in these cancer types is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify the most frequently deleted region on chromosome 9p21 in human malignant cell lines.
  • To characterize the gene located within this deleted region and investigate its potential role in cancer development.
  • To determine the frequency of alterations and expression of this gene in various cancers.

Main Methods:

  • Positional cloning was used to localize the frequently deleted region on 9p21 from a panel of 46 human malignant cell lines.
  • Sequence analysis was performed on the isolated DNA fragment to identify open reading frames.
  • Polymerase chain reaction (PCR) and Southern blot analysis were employed to assess gene deletion, rearrangement, and transcript presence in tumor samples.

Main Results:

  • The most frequently deleted region on 9p21 was localized and found to contain the gene for the inhibitor of cyclin-dependent kinase 4 (CDK4).
  • Frequent deletion or rearrangement of the CDK4-inhibitor gene was confirmed in melanomas, gliomas, lung cancers, and leukaemias, with absence of detectable gene transcripts.
  • A germ-line nonsense mutation in the CDK4-inhibitor gene was identified in a patient with dysplastic nevus syndrome.

Conclusions:

  • The CDK4-inhibitor gene is frequently altered in various cancers, suggesting its role as a tumor suppressor.
  • Loss or inactivation of the CDK4 inhibitor may contribute to uncontrolled cell proliferation and neoplastic transformation.
  • Further investigation into the CDK4 inhibitor's function could reveal new therapeutic targets for cancer treatment.

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