Skip to main content
Journal cover image

Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma.

Publication ,  Journal Article
Kratzke, RA; Otterson, GA; Lincoln, CE; Ewing, S; Oie, H; Geradts, J; Kaye, FJ
Published in: J Natl Cancer Inst
December 20, 1995

BACKGROUND: The identification in 1994 of the CDKN2 gene as a target for mutations in a wide range of human cancers, including malignant mesothelioma, has been controversial because subsequent studies have detected a lower frequency of CDKN2 gene mutations in primary tumors than in cultured cell lines. These reports raised the hypothesis that another gene, distinct from CDKN2, might be the target of the chromosome 9p21 deletions frequently observed in these tumors. PURPOSE: To address whether inactivation of CDKN2 function is an essential event in the etiology of malignant mesothelioma, we examined p16INK4 protein expression in primary thoracic mesotheliomas, in nonmalignant pleural tissues, and in independent mesothelioma cell lines. We also studied the growth rate of tumor cell lines following stable transfection of CDKN2 gene. METHODS: Retinoblastoma (Rb) and p16INK4 protein expression was determined by immunohistochemical analysis from archival paraffin specimens of 12 primary thoracic mesotheliomas and a nonmalignant pleural biopsy specimen. In addition, protein immunoblot analysis for Rb and p16INK4 expression was conducted on 15 independent mesothelioma cell lines, and the ability of a transfected CDKN2 gene to suppress the growth of the mesothelioma cell lines H2373 and H2461 in vitro was examined. RESULTS: We demonstrated abnormal p16INK4 expression in 12 of 12 primary mesothelioma specimens and in 15 of 15 mesothelioma cell lines. All tumor specimens and the tumor cell lines showed expression of wild-type Rb protein. In addition, we have confirmed the ability of a transfected CDKN2 gene to suppress growth of two independent mesothelioma cell lines. CONCLUSIONS: Immunohistochemical analysis of the p16INK4 gene product is feasible in archival biopsy samples. With this analysis, CDKN2 gene inactivation can be determined in tumors that are contaminated with nonmalignant cells. Furthermore, since loss of p16INK4 protein expression can result from both genetic (gene mutations) and epigenetic (abnormal DNA hypermethylation) mechanisms, as we and others have shown recently, examination of protein expression is a highly sensitive method for analyzing the CDKN2 status in large numbers of tumor samples. IMPLICATIONS: This study suggests that inactivation of the CDKN2 gene is an essential step in the etiology of malignant mesotheliomas. Defining the role of the p16INK4:Rb tumor suppressor pathway and its immediate downstream substrates will be an important goal in designing future therapeutic strategies.

Duke Scholars

Published In

J Natl Cancer Inst

DOI

ISSN

0027-8874

Publication Date

December 20, 1995

Volume

87

Issue

24

Start / End Page

1870 / 1875

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Retinoblastoma Protein
  • Oncology & Carcinogenesis
  • Mesothelioma
  • Immunohistochemistry
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Cyclin-Dependent Kinase Inhibitor p16
  • Carrier Proteins
  • 3211 Oncology and carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kratzke, R. A., Otterson, G. A., Lincoln, C. E., Ewing, S., Oie, H., Geradts, J., & Kaye, F. J. (1995). Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma. J Natl Cancer Inst, 87(24), 1870–1875. https://doi.org/10.1093/jnci/87.24.1870
Kratzke, R. A., G. A. Otterson, C. E. Lincoln, S. Ewing, H. Oie, J. Geradts, and F. J. Kaye. “Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma.J Natl Cancer Inst 87, no. 24 (December 20, 1995): 1870–75. https://doi.org/10.1093/jnci/87.24.1870.
Kratzke RA, Otterson GA, Lincoln CE, Ewing S, Oie H, Geradts J, et al. Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma. J Natl Cancer Inst. 1995 Dec 20;87(24):1870–5.
Kratzke, R. A., et al. “Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma.J Natl Cancer Inst, vol. 87, no. 24, Dec. 1995, pp. 1870–75. Pubmed, doi:10.1093/jnci/87.24.1870.
Kratzke RA, Otterson GA, Lincoln CE, Ewing S, Oie H, Geradts J, Kaye FJ. Immunohistochemical analysis of the p16INK4 cyclin-dependent kinase inhibitor in malignant mesothelioma. J Natl Cancer Inst. 1995 Dec 20;87(24):1870–1875.
Journal cover image

Published In

J Natl Cancer Inst

DOI

ISSN

0027-8874

Publication Date

December 20, 1995

Volume

87

Issue

24

Start / End Page

1870 / 1875

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Retinoblastoma Protein
  • Oncology & Carcinogenesis
  • Mesothelioma
  • Immunohistochemistry
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Cyclin-Dependent Kinase Inhibitor p16
  • Carrier Proteins
  • 3211 Oncology and carcinogenesis