Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

Esteller, Manel; Herman, James G.

doi:10.1038/sj.onc.1207316

Cited by 272 publications

(199 citation statements)

References 87 publications

(82 reference statements)

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“…Ten percent of colorectal tumours have simultaneous silencing of both genes, and this phenomenon confers 44 resistance to cell death, producing a high incidence of mutation. Although tumours with methylated MGMT are more sensitive to the apoptotic effects of alkylating agents, it has been reported that Mgmt À/À mice with a loss of MLH1 expres- DNA repair genes in monoclonal gammopathies P Martin et al sion 45,46 are as resistant to alkylating drugs as are wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

et al. 2006

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Monoclonal gammopathies are a group of disorders characterized by clonal proliferation and accumulation of immunoglobulin-producing plasma cells. Multiple myeloma and monoclonal gammopathy of undetermined significance are the most common monoclonal gammopathies; the two comprise a spectrum of disorders, ranging from a relatively benign disease, monoclonal gammopathy of undetermined significance, to a malignant disease, multiple myeloma. Aberrant promoter methylation represents a primary mechanism of gene silencing during tumorigenesis. DNA repair systems act to maintain genome integrity in the presence of replication errors, environmental insults, and the cumulative effects of aging. The methylation patterns of two genes implicated in DNA repair, O6 methylguanine DNA methyl-transferase (MGMT) and human mutL homologue1 (hMLH1) have been detected in various solid tumours. With the purpose of studying the gene silencing of MGMT and hMLH1 in plasma cell disorders, we investigated the methylation status and expression of both genes in: 29 cases of multiple myeloma; one case of plasma cell leukaemia; 13 cases of monoclonal gammopathy of undetermined significance; and two cases of polyclonal plasmacytosis, using methylationspecific polymerase-chain reaction and immunohistochemical techniques. Methylation frequencies for MGMT were 23% in multiple myeloma and 8% in monoclonal gammopathy of undetermined significance. It was 10% for hMLH1 in multiple myeloma. None of the patients diagnosed with monoclonal gammopathy of undetermined significance had hMLH1 hypermethylated. In addition, 50% of myeloma cases had a loss of hMLH1 expression, whereas silencing of MGMT was observed in 43% of myeloma and 36% of samples with monoclonal gammopathy of undetermined significance. This study indicates that repair pathway defects play a role in the pathogenesis and evolution of monoclonal gammopathies, and suggests that inactivation of hMLH1 could be implicated in multiple myeloma tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

et al. 2006

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“…One of the most plausible candidates for a gene whose inactivation may initiate carcinogenesis is MGMT, which codes for a protein that removes alkyl adducts from the O6 position of guanine (5). Loss of MGMT function will give rise to a mutator phenotype, as alkylation damage from a variety of environmental sources is a common occurrence and as alkylated guanine is likely to mispair with thymine during DNA replication.…”

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confidence: 99%

Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism

Candiloro

Dobrovic

2009

Cancer Prevention Research

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Methylation of the CpG island in the MGMT promoter region is a frequent event in several cancer types including colorectal cancer, lung cancer, lymphoma, and glioblastoma. A correlation between methylation and the T allele of the rs16906252 single nucleotide polymorphism (SNP) in colorectal carcinomas has previously been reported. As aberrant MGMT methylation can be an early event in tumor development, we tested the hypothesis that normal individuals possessing the T allele may be predisposed to somatic methylation at the MGMT promoter. Peripheral blood monononuclear cell DNA from 89 normal, healthy individuals was genotyped at rs1690625 and assessed for the methylation status of the MGMT promoter region using independent quantitative methodologies capable of detecting lowlevel methylation: MethyLight and Sensitive Melting Analysis after Real-time MethylationSpecific PCR (SMART-MSP). There was a strong association between presence of the T allele and detectable methylation (P = 0.00005) in the peripheral blood DNA. Furthermore, when a MSP assay flanking the SNP was used to amplify methylated sequences in heterozygotes, only the T allele was methylated. Thus, detectable somatic methylation of the MGMT promoter in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter SNP.Inactivation of tumor suppressor genes and DNA stability genes by promoter methylation is a common occurrence in human cancer. In some cases, epigenetic inactivation of one of these genes is likely to be the initiating event in cancer development (reviewed in ref. 1). Evidence for this is particularly strong for certain hereditary cancer genes where constitutional methylation of the gene predisposes to cancer development (2-4).It is also likely that constitutional methylation of other genes not normally involved in heritable cancer can predispose to cancer. One of the most plausible candidates for a gene whose inactivation may initiate carcinogenesis is MGMT, which codes for a protein that removes alkyl adducts from the O6 position of guanine (5). Loss of MGMT function will give rise to a mutator phenotype, as alkylation damage from a variety of environmental sources is a common occurrence and as alkylated guanine is likely to mispair with thymine during DNA replication. MGMT methylation is commonly found in various cancers including colorectal cancers, gliomas, head and neck cancers, and lymphomas (6). MGMT promoter methylation has been used as a predictive marker in cancers; it indicates those individuals who are likely to respond to chemotherapy with alkylating agents (7,8).MGMT methylation may be an early or even predisposing event in colorectal cancer. Esteller et al. (9) reported that MGMT methylation was present in adenomas. Shen et al. (10) reported that MGMT methylation was found in apparently normal colonic tissue up to 10 cm from an MGMT-methylated colorectal cancer indicating that MGMT methylation can even be observed prior to any detectable change in morphology.Ogino et al. (11) investi...

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“…Tumors displaying MGMT promoter methylation are more sensitive to the killing effects of the nitrosourea-type alkylating drugs used in chemotherapy. 28 In support of the MGMT role in malignant conversion, Becker et al 16 have shown recently that overexpression of MGMT in mouse skin reduced the MNU-induced conversion from papillomas to carcinomas by 4-fold. Baylin and Herman 24 have reviewed the role of several genes regulated by CpG methylation and stressed that ''.…”

Section: Discussionmentioning

confidence: 97%

“…28 In the development of human colon cancer, methylation of MGMT, an early step in the process, is associated with the subsequent development of G-A transition mutations in Ki-ras. 7 In pancreatic carcinomas, however, there was no association between a high rate of Ki-ras mutations and MGMT promoter methylation.…”

Section: Discussionmentioning

confidence: 99%

Methylation of the O⁶‐methylguanine‐DNA methyltransferase promoter suppresses expression in mouse skin tumors and varies with the tumor induction protocol

Abdel-Fattah¹,

Glick²,

Rehman³

et al. 2005

Intl Journal of Cancer

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Hypermethylation of CpG sites within the promoter region of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene occurs frequently in human cancer, preventing both MGMT expression and repair of alkylation damage. To assess the role of MGMT in the development of mouse skin tumors induced by initiationpromotion protocols, methylation of the MGMT promoter was examined in tumor DNA using methylation-specific PCR. To determine whether MGMT promoter methylation was affected by the tumor induction protocol, tumors were initiated by N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) or 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA) or mezerein. Although the MGMT promoter was not methylated in normal skin, promoter methylation was found in 56 of 136 papillomas (41.2%) and in 19 of 37 squamous cell carcinomas (51.4%). When methylation of the MGMT promoter was compared in the 4 treatment groups, hypermethylation was found more frequently in tumors initiated by DMBA and promoted by mezerein, a protocol associated with a high frequency of malignant conversion. Methylation was found in some tumors as early as 5 weeks after initiation, but the methylation frequency increased with time. MGMT promoter methylation reduced MGMT expression as determined by immunohistochemistry. Although MGMT promoter methylation was not generally correlated with ras mutations, the frequency of MGMT methylation was higher in MNNGinitiated, mezerein-promoted papillomas with mutations in Ha-ras compared to papillomas with Ki-ras. Methylation of the MGMT promoter, associated with reduced MGMT expression, is found in nearly half of mouse skin tumors, but varies with both the tumor initiator and tumor promoter, and may be a key step in the progression from papillomas to carcinomas. ' 2005 Wiley-Liss, Inc.Key words: methylation; MGMT; skin tumors; papillomas; carcinomas MNNG and other alkylating agents induce O 6 -alkylguanine DNA adducts that are important in tumor induction 1 and can be repaired by the DNA repair enzyme MGMT. MGMT irreversibly transfers the methyl group of O 6 -methylguanine to a specific cysteine residue within its own sequence, thereby restoring guanine and preventing G-A base substitutions. The level of MGMT per cell, which determines the rate of repair of O 6 -methylguanine, affects the susceptibility to the mutagenic and carcinogenic effects of alkylating carcinogens. 2-4 MGMT expression is reduced by hypermethylation of CpG islands within the promoter region of MGMT in primary human carcinomas 5 and in transformed human cell lines in culture. 6 Inactivation of the MGMT gene has been associated with G-A mutations in the Ki-ras oncogene 7 and the p53 tumor suppressor gene in human colorectal tumors. 8 The importance of MGMT in tumor development has been verified in studies using genetically-engineered MGMT transgenic and knockout mice. Overexpression of human or E. coli MGMT prevents G-A mutations and protects mice from tumorigenesis after treatment with alkylating agents. 9-11 Transg...

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Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

Cited by 272 publications

References 87 publications

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism

Methylation of the O⁶‐methylguanine‐DNA methyltransferase promoter suppresses expression in mouse skin tumors and varies with the tumor induction protocol

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Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

Cited by 272 publications

References 87 publications

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism

Methylation of the O6‐methylguanine‐DNA methyltransferase promoter suppresses expression in mouse skin tumors and varies with the tumor induction protocol

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Methylation of the O⁶‐methylguanine‐DNA methyltransferase promoter suppresses expression in mouse skin tumors and varies with the tumor induction protocol