Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma

Lei Zhang, Wenfu Lu, Xiaoping Miao, Deyin Xing, Wen Tan, Dongxin Lin

Research output: Contribution to journalReview article

Abstract

The development of esophageal squamous cell carcinoma (ESCC) has been linked to exposure to carcinogens such as nitrosamines that cause various alkyl DNA damages and O6-methylguanine-DNA methyltransferase (MGMT) is a primary defence against alkylation-induced mutagenesis and carcinogenesis. This study was to investigate the role of inactivation of MGMT by promoter hypermethylation and its relation to p53 mutations in ESCC. Methylation of MGMT promoter was determined by methylation-specific polymerase chain reaction in 119 ESCC specimens, 22 corresponding tissue samples adjacent to the tumors, and 21 normal epithelial specimens of the esophagus. The levels of MGMT protein in ESCC with methylated or unmethylated MGMT were analyzed by quantitative immunohistochemistry. Mutations of p53 in 119 ESCC were detected by denaturing high-performance liquid chromatography and sequencing. We found that all 21 normal esophageal tissues had unmethylated MGMT; however, among 119 ESCC, 46 (38.7%) had hypermethylated MGMT. This epigenetic change also occurred in some normal tissues adjacent to the tumors. The level of MGMT protein in MGMT-methylated ESCC was significantly lower than that in MGMT-unmethylated ESCC, whereas great inter-individual variation and poor expression was also observed among MGMT-unmethylated ESCC. Fifty-one percent (61/119) ESCC showed p53 mutations but the distribution of the mutations did not differ significantly between MGMT-methylated ESCC (44%) and MGMT-unmethylated ESCC (56.2%; P = 0.18). MGMT promoter hypermethylation was neither associated with overall G:C to A:T mutations nor associated with this type of mutations in non-CpG dinucleotides in p53. Our results demonstrate that inactivation of MGMT by aberrant promoter methylation is a frequent molecular event in ESCC. This epigenetic alteration is an important, but may not be the sole, mechanism leading to the impaired expression of MGMT. Aberrant MGMT methylation seemed not to be associated with overall frequency and spectrum of p53 mutations in ESCC.

Original languageEnglish (US)
Pages (from-to)1039-1044
Number of pages6
JournalCarcinogenesis
Volume24
Issue number6
StatePublished - Jun 1 2003
Externally publishedYes

Fingerprint

Methyltransferases
DNA Repair
Mutation
DNA
Genes
Protein Methyltransferases
O-(6)-methylguanine
Esophageal Squamous Cell Carcinoma
DNA Methylation
Epigenomics
Methylation
Nitrosamines
Alkylation
Mutagenesis
Carcinogens
Esophagus
DNA Damage
Neoplasms
Carcinogenesis

ASJC Scopus subject areas

  • Cancer Research

Cite this

Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma. / Zhang, Lei; Lu, Wenfu; Miao, Xiaoping; Xing, Deyin; Tan, Wen; Lin, Dongxin.

In: Carcinogenesis, Vol. 24, No. 6, 01.06.2003, p. 1039-1044.

Research output: Contribution to journalReview article

@article{3d969a911395428ea7399e340a0a108d,
title = "Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma",
abstract = "The development of esophageal squamous cell carcinoma (ESCC) has been linked to exposure to carcinogens such as nitrosamines that cause various alkyl DNA damages and O6-methylguanine-DNA methyltransferase (MGMT) is a primary defence against alkylation-induced mutagenesis and carcinogenesis. This study was to investigate the role of inactivation of MGMT by promoter hypermethylation and its relation to p53 mutations in ESCC. Methylation of MGMT promoter was determined by methylation-specific polymerase chain reaction in 119 ESCC specimens, 22 corresponding tissue samples adjacent to the tumors, and 21 normal epithelial specimens of the esophagus. The levels of MGMT protein in ESCC with methylated or unmethylated MGMT were analyzed by quantitative immunohistochemistry. Mutations of p53 in 119 ESCC were detected by denaturing high-performance liquid chromatography and sequencing. We found that all 21 normal esophageal tissues had unmethylated MGMT; however, among 119 ESCC, 46 (38.7{\%}) had hypermethylated MGMT. This epigenetic change also occurred in some normal tissues adjacent to the tumors. The level of MGMT protein in MGMT-methylated ESCC was significantly lower than that in MGMT-unmethylated ESCC, whereas great inter-individual variation and poor expression was also observed among MGMT-unmethylated ESCC. Fifty-one percent (61/119) ESCC showed p53 mutations but the distribution of the mutations did not differ significantly between MGMT-methylated ESCC (44{\%}) and MGMT-unmethylated ESCC (56.2{\%}; P = 0.18). MGMT promoter hypermethylation was neither associated with overall G:C to A:T mutations nor associated with this type of mutations in non-CpG dinucleotides in p53. Our results demonstrate that inactivation of MGMT by aberrant promoter methylation is a frequent molecular event in ESCC. This epigenetic alteration is an important, but may not be the sole, mechanism leading to the impaired expression of MGMT. Aberrant MGMT methylation seemed not to be associated with overall frequency and spectrum of p53 mutations in ESCC.",
author = "Lei Zhang and Wenfu Lu and Xiaoping Miao and Deyin Xing and Wen Tan and Dongxin Lin",
year = "2003",
month = "6",
day = "1",
language = "English (US)",
volume = "24",
pages = "1039--1044",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma

AU - Zhang, Lei

AU - Lu, Wenfu

AU - Miao, Xiaoping

AU - Xing, Deyin

AU - Tan, Wen

AU - Lin, Dongxin

PY - 2003/6/1

Y1 - 2003/6/1

N2 - The development of esophageal squamous cell carcinoma (ESCC) has been linked to exposure to carcinogens such as nitrosamines that cause various alkyl DNA damages and O6-methylguanine-DNA methyltransferase (MGMT) is a primary defence against alkylation-induced mutagenesis and carcinogenesis. This study was to investigate the role of inactivation of MGMT by promoter hypermethylation and its relation to p53 mutations in ESCC. Methylation of MGMT promoter was determined by methylation-specific polymerase chain reaction in 119 ESCC specimens, 22 corresponding tissue samples adjacent to the tumors, and 21 normal epithelial specimens of the esophagus. The levels of MGMT protein in ESCC with methylated or unmethylated MGMT were analyzed by quantitative immunohistochemistry. Mutations of p53 in 119 ESCC were detected by denaturing high-performance liquid chromatography and sequencing. We found that all 21 normal esophageal tissues had unmethylated MGMT; however, among 119 ESCC, 46 (38.7%) had hypermethylated MGMT. This epigenetic change also occurred in some normal tissues adjacent to the tumors. The level of MGMT protein in MGMT-methylated ESCC was significantly lower than that in MGMT-unmethylated ESCC, whereas great inter-individual variation and poor expression was also observed among MGMT-unmethylated ESCC. Fifty-one percent (61/119) ESCC showed p53 mutations but the distribution of the mutations did not differ significantly between MGMT-methylated ESCC (44%) and MGMT-unmethylated ESCC (56.2%; P = 0.18). MGMT promoter hypermethylation was neither associated with overall G:C to A:T mutations nor associated with this type of mutations in non-CpG dinucleotides in p53. Our results demonstrate that inactivation of MGMT by aberrant promoter methylation is a frequent molecular event in ESCC. This epigenetic alteration is an important, but may not be the sole, mechanism leading to the impaired expression of MGMT. Aberrant MGMT methylation seemed not to be associated with overall frequency and spectrum of p53 mutations in ESCC.

AB - The development of esophageal squamous cell carcinoma (ESCC) has been linked to exposure to carcinogens such as nitrosamines that cause various alkyl DNA damages and O6-methylguanine-DNA methyltransferase (MGMT) is a primary defence against alkylation-induced mutagenesis and carcinogenesis. This study was to investigate the role of inactivation of MGMT by promoter hypermethylation and its relation to p53 mutations in ESCC. Methylation of MGMT promoter was determined by methylation-specific polymerase chain reaction in 119 ESCC specimens, 22 corresponding tissue samples adjacent to the tumors, and 21 normal epithelial specimens of the esophagus. The levels of MGMT protein in ESCC with methylated or unmethylated MGMT were analyzed by quantitative immunohistochemistry. Mutations of p53 in 119 ESCC were detected by denaturing high-performance liquid chromatography and sequencing. We found that all 21 normal esophageal tissues had unmethylated MGMT; however, among 119 ESCC, 46 (38.7%) had hypermethylated MGMT. This epigenetic change also occurred in some normal tissues adjacent to the tumors. The level of MGMT protein in MGMT-methylated ESCC was significantly lower than that in MGMT-unmethylated ESCC, whereas great inter-individual variation and poor expression was also observed among MGMT-unmethylated ESCC. Fifty-one percent (61/119) ESCC showed p53 mutations but the distribution of the mutations did not differ significantly between MGMT-methylated ESCC (44%) and MGMT-unmethylated ESCC (56.2%; P = 0.18). MGMT promoter hypermethylation was neither associated with overall G:C to A:T mutations nor associated with this type of mutations in non-CpG dinucleotides in p53. Our results demonstrate that inactivation of MGMT by aberrant promoter methylation is a frequent molecular event in ESCC. This epigenetic alteration is an important, but may not be the sole, mechanism leading to the impaired expression of MGMT. Aberrant MGMT methylation seemed not to be associated with overall frequency and spectrum of p53 mutations in ESCC.

UR - http://www.scopus.com/inward/record.url?scp=0038687773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038687773&partnerID=8YFLogxK

M3 - Review article

C2 - 12807758

AN - SCOPUS:0038687773

VL - 24

SP - 1039

EP - 1044

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 6

ER -