Inactivation of p16INK4a expression in malignant mesothelioma by methylation

Long Wong, Joan Zhou, Daniel Anderson, Robert A. Kratzke

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Abstract

The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16INK4a. Absence of expression of the p16INK4a gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16INK4a expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16INK4a expression is known to be inactivated by hypermethylation of the first exon. In a survey of ten mesothelioma cell lines, one cell line (NCI-H2596) was identified as possessing loss of p16INK4a gene product following gene methylation. This methylation in these mesothelioma cells could be reversed, resulting in re-expression of p16INK4a protein, following the treatment of the cells with cytidine analogs, which are known inhibitors of DNA methylation. In previous clinical trials in mesothelioma, the cytidine analog dihydro-5-azacytidine (DHAC) has been found to induce clinical responses in approximately 17% of patients with mesothelioma treated with this drug, including prolonged complete responses. In addition, we identified evidence for methylation of p16INK4a in three of 11 resected mesothelioma tumor samples. When both cell lines and tumors are combined, inactivation of p16INK4a gene product expression following DNA hypermethylation was found in four of 21 samples (19%). We are further exploring the clinical significance of inhibition of methylation in mesothelioma by cytidine analogs. This may provide a potential treatment target in some mesothelioma tumors by inhibition of methylation.

Original languageEnglish
Pages (from-to)131-136
Number of pages6
JournalLung Cancer
Volume38
Issue number2
DOIs
StatePublished - 1 Nov 2002

Fingerprint

Mesothelioma
Methylation
p16 Genes
Cytidine
5,6-dihydro-5-azacytidine
Tumor Cell Line
Lung Neoplasms
Neoplasms
Cyclin-Dependent Kinase Inhibitor p16
Malignant Mesothelioma
Cell Line
DNA Methylation
Exons
Carcinogenesis
Clinical Trials
Gene Expression
DNA
Therapeutics
Growth

Keywords

  • Cell cycle
  • Epigenetic
  • cdk

Cite this

Wong, Long ; Zhou, Joan ; Anderson, Daniel ; Kratzke, Robert A. / Inactivation of p16INK4a expression in malignant mesothelioma by methylation. In: Lung Cancer. 2002 ; Vol. 38, No. 2. pp. 131-136.
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Inactivation of p16INK4a expression in malignant mesothelioma by methylation. / Wong, Long; Zhou, Joan; Anderson, Daniel; Kratzke, Robert A.

In: Lung Cancer, Vol. 38, No. 2, 01.11.2002, p. 131-136.

Research output: Contribution to journalArticleResearchpeer-review

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