Inactivation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia

Manel Esteller, Stanley R. Hamilton, Peter C. Burger, Stephen B Baylin, James G. Herman

Research output: Contribution to journalArticle

Abstract

The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the 06 position of guanine. MGMT expression is decreased in some tumor tissues, and lack of activity has been observed in some cell lines. Loss of expression is rarely due to deletion, mutation, or rearrangement of the MGMT gene, but methylation of discrete regions of the CpG island of MGMT has been associated with the silencing of the gene in cell lines. We used methylation-specific PCR to study the promoter methylation of the MGMT gene. All normal tissues and expressing cancer cell lines were unmethylated, whereas nonexpressing cancer cell lines were methylated. Among the more than 500 primary human tumors examined, MGMT hypermethylation was present in a subset of specific types of cancer. In gliomas and colorectal carcinomas, aberrant methylation was detected in 40% of the tumors, whereas in non-small cell lung carcinomas, lymphomas, and head and neck carcinomas, this alteration was found in 25% of the tumors. MGMT methylation was found rarely or not at all in other tumor types. We also analyzed MGMT expression by immunohistochemistry in relation to the methylation status in 31 primary tumors. The presence of aberrant hypermethylation was associated with loss of MGMT protein, in contrast to retention of protein in the majority of tumors without aberrant hypermethylation. Our results suggest that epigenetic inactivation of MGMT plays an important role in primary human neoplasia.

Original languageEnglish (US)
Pages (from-to)793-797
Number of pages5
JournalCancer Research
Volume59
Issue number4
StatePublished - Feb 15 1999

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O(6)-Methylguanine-DNA Methyltransferase
DNA Repair
Methyltransferases
Genes
Neoplasms
DNA
Methylation
Cell Line
DNA Methylation
Protein Methyltransferases
CpG Islands
Gene Rearrangement
Sequence Deletion
Guanine
Gene Silencing
Epigenomics
Non-Small Cell Lung Carcinoma
Glioma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inactivation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. / Esteller, Manel; Hamilton, Stanley R.; Burger, Peter C.; Baylin, Stephen B; Herman, James G.

In: Cancer Research, Vol. 59, No. 4, 15.02.1999, p. 793-797.

Research output: Contribution to journalArticle

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