Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma

Yu Jing Zhang, Yu Chen, Habibul Ahsan, Ruth M. Lunn, Po Huang Lee, Chien Jen Chen, Regina M. Santella

Research output: Contribution to journalArticle

Abstract

O6-methylguanine-DNA methyltransferase (MGMT) is a repair protein that specifically removes promutagenic alkyl groups from the O6 position of guanine in DNA. MGMT is transcriptionally silenced by promoter hypermethylation in several human cancers. Methylation-specific PCR (MSP) was used to analyze the MGMT promoter methylation status of 83 hepatocellular carcinomas (HCC) and 2 HCC cell lines (HepG2 and Hep3B). Hypermethylation was detected in 32 of 83 (39%) HCC tissues, but it was not found in either HCC cell line. We also analyzed MGMT expression by immunohistochemical analysis of HCC tissue samples. The presence of aberrant hypermethylation was associated with loss of MGMT protein. The relationship between methylation status and risk factors and tumor markers including environmental exposure to aflatoxin B1 (AFB1), measured as DNA adducts, and status of tumor suppressor gene p53 was also investigated. A statistically significant association was found between MGMT promoter hypermethylation and high level of AFB1-DNA adducts in tumor tissues (OR = 5.05, 95% CI = 1.29-19.73). A significant association was also found between methylation and p53 mutation status (OR = 2.97, 95% CI = 1.09-8.11). These results suggest that epigenetic inactivation of MGMT plays an important role in the development of HCC and exposure to environmental carcinogens may be related to altered methylation of genes involved in cancer development. The role of chemical carcinogens in hypermethylation needs further investigation.

Original languageEnglish (US)
Pages (from-to)440-444
Number of pages5
JournalInternational Journal of Cancer
Volume103
Issue number4
DOIs
StatePublished - Feb 10 2003

Keywords

  • CpG island
  • Epigenetic changes
  • Hepatocellular carcinoma
  • Hypermethylation
  • O-methylguanine-DNA methyltransferase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Inactivation of the DNA repair gene O<sup>6</sup>-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B<sub>1</sub>-DNA adducts and p53 mutation in hepatocellular carcinoma'. Together they form a unique fingerprint.

  • Cite this