J Korean Orthop Assoc.  2003 Oct;38(6):631-640.

Significance of the Methylation of Cyclin-Dependent Kinase Inhibitor 2A gene in the Prognosis of Osteosarcoma

• Oh JH
• Lee SH
• Suh SW
• Cho HS
• Kim JH
• Kim JE
• Kim HS

Abstract

PURPOSE
The methylation status of the CpG promoter regions of the p16INK4A and p14ARF genes, mutations of 4 exons of the CDKN2A gene, and the expression of the corresponding proteins were examined. Prognostic implications were assessed in osteosarcoma. MATERIALS AND METHODS: Methylation-specific PCR, sequence analysis, and immunohistochemical staining were performed upon 32 frozen osteosarcoma tissues. RESULTS: Methylation of p16INK4A was found in 16%, and methylation of p14ARF in 47%. Metastasis and poor survival was statistically related to the methylation of p14ARF. The methylation of p14ARF correlated with the repression of the corresponding protein, and repression of p14ARF with the repression of p21 and of wild type of p53. No sequence alterations were found in the four exons of the CDKN2A gene. Methylation of p14 showed highest hazard ratio by multivariate survival analysis. CONCLUSION: Our data suggest that methylation of the CDKN2A gene seems to be the main mechanism of protein repression. For p14ARF, the methylation of its promoter region was related to the repression of p21 and wild type p53, distant metastasis and a poor prognosis. Further study regarding cell cycle regulatory factors should shed light on oncogenesis and the possibility of a new treatment strategy for osteosarcoma.

Keyword

Osteosarcoma; CDKN2A gene; p14ARF; Methylation; Prognosis

MeSH Terms

Carcinogenesis
Cell Cycle
Exons
Genes, p16
Methylation*
Neoplasm Metastasis
Osteosarcoma*
Phosphotransferases*
Polymerase Chain Reaction
Prognosis*
Promoter Regions, Genetic
Repression, Psychology
Sequence Analysis
Tumor Suppressor Protein p14ARF
Phosphotransferases
Tumor Suppressor Protein p14ARF