HGNC Approved Gene Symbol: MGMT
Cytogenetic location: 10q26.3 Genomic coordinates (GRCh38): 10:129,467,241-129,770,983 (from NCBI)
O(6)-alkylguanine is the major mutagenic and carcinogenic lesion in DNA induced by simple alkylating mutagens because of its preference for pairing with thymine during DNA replication. This adduct in DNA is removed by a ubiquitous and unique repair protein, O(6)-methylguanine-DNA methyltransferase (EC 2.1.1.63). This protein, unlike true enzymes, accepts the alkyl group from the lesion in a stoichiometric second-order reaction. The methyl-acceptor residue is cysteine. Tano et al. (1990) cloned the cDNA of the human MGMT gene in an expression vector on the basis of its rescue of a methyltransferase-deficient E. coli host.
Rydberg et al. (1990) concluded that the methyltransferase gene spans at least 15 kb.
By study of DNA from mouse/human hybrid cell lines, Rydberg et al. (1990) mapped the MGMT gene to chromosome 10. Zunino et al. (1991) likewise mapped the MGMT gene to chromosome 10 by study of somatic cell hybrids. Using a panel of 5 human/rodent cell hybrids that divide chromosome 10 into 6 regions, Gardner et al. (1991) refined the localization of the gene to 10q24.33-qter. By nonradioactive in situ hybridization, Natarajan et al. (1992) mapped the MGMT gene to 10q26.
Esteller et al. (2000) analyzed the MGMT promoter in tumor DNA by a methylation-specific PCR assay to determine whether methylation of the MGMT promoter is related to the responsiveness of gliomas (137800) to alkylating agents. The MGMT promoter was methylated in gliomas from 19 of 47 patients (40%). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status. The authors concluded that methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.
In an evaluation of combined radiotherapy and temozolomide for newly diagnosed glioblastoma, Hegi et al. (2004) found that methylation of the MGMT promoter in the tumor was associated with longer survival. Stupp et al. (2005) showed that the addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Hegi et al. (2005) studied methylation of the MGMT promoter in newly diagnosed glioblastomas and found that patients with a methylated MGMT promoter in the glioblastoma benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
Testicular germ cell tumors are classified into 2 major histologic subgroups, seminomas and nonseminomas. In a series of 70 testicular germ cell tumors, Smith-Sorensen et al. (2002) analyzed for methylation of CpG sites in the MGMT gene promoter and in exon 1-alpha of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A; 600160). None of 55 tumors showed methylation of CDKN2A. On the other hand, high frequencies of MGMT promoter methylation and allelic imbalances at 10q markers were found in 32 of 69 (46%) and 50 of 70 (71%) tumors, respectively. A significantly higher methylation frequency was found in 24 of 35 nonseminomas (69%) compared to 8 of 33 seminomas (24%). Immunohistochemical analysis of the MGMT protein in a subgroup of the testicular tumors supported the hypothesis of gene silencing being the functional consequence of the promoter methylation. The data suggested that inactivation of MGMT contributes to the development of nonseminomatous testicular cancer.
By examining gene expression profiles, Fry et al. (2008) showed that elevated MGMT expression was associated with reduced sensitivity to MNNG, a DNA alkylating agent. Analysis of genes that were differentially expressed between cell lines with the highest and lowest MNNG sensitivities integrated MGMT into a protein network related to human cancer and tumorigenesis.
The Cancer Genome Atlas Research Network (2008) reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. A link was found between MGMT promoter methylation and hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas. The methylation status of MGMT predicts sensitivity to temozolomide, an alkylating agent used to treat glioblastoma patients. In those patients who also have mutation in the mismatch repair pathway, treatment with an alkylating agent was associated with characteristic C-G and A-T transversions in non-CpG sites, raising the possibility that patients who initially respond to treatment with alkylating agents may evolve not only treatment resistance but also a mismatch repair-defective hypermutator phenotype.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061-1068, 2008. Note: Erratum: Nature 494: 506 only, 2013. [PubMed: 18772890] [Full Text: https://doi.org/10.1038/nature07385]
Esteller, M., Garcia-Foncillas, J., Andion, E., Goodman, S. N., Hidalgo, O. F., Vanaclocha, V., Baylin, S. B., Herman, J. G. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New Eng. J. Med. 343: 1350-1354, 2000. Note: Erratum: New Eng. J. Med. 343: 1740 only, 2000. [PubMed: 11070098] [Full Text: https://doi.org/10.1056/NEJM200011093431901]
Fry, R. C., Svensson, J. P., Valiathan, C., Wang, E., Hogan, B. J., Bhattacharya, S., Bugni, J. M., Whittaker, C. A., Samson, L. D. Genomic predictors of interindividual differences in response to DNA damaging agents. Genes Dev. 22: 2621-2626, 2008. [PubMed: 18805990] [Full Text: https://doi.org/10.1101/gad.1688508]
Gardner, E., Rydberg, B., Karran, P., Ponder, B. A. J. Localization of the human O(6)-methylguanine-DNA methyltransferase gene to chromosome 10q24.33-qter. Genomics 11: 475-476, 1991. [PubMed: 1769664] [Full Text: https://doi.org/10.1016/0888-7543(91)90162-8]
Hegi, M. E., Diserens, A.-C., Godard, S., Dietrich, P.-Y., Regli, L., Ostermann, S., Otten, P., Van Melle, G., de Tribolet, N., Stupp, R. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin. Cancer Res. 10: 1871-1874, 2004. [PubMed: 15041700] [Full Text: https://doi.org/10.1158/1078-0432.ccr-03-0384]
Hegi, M. E., Diserens, A.-C., Gorlia, T., Hamou, M.-F., de Tribolet, N., Weller, M., Kros, J. M., Hainfellner, J. A., Mason, W., Mariani, L., Bromberg, J. E. C., Hau, P., Mirimanoff, R. O., Cairncross, J. G., Janzer, R. C., Stupp, R. MGMT gene silencing and benefit from temozolomide in glioblastoma. New Eng. J. Med. 352: 997-1003, 2005. [PubMed: 15758010] [Full Text: https://doi.org/10.1056/NEJMoa043331]
Natarajan, A. T., Vermeulen, S., Darroudi, F., Valentine, M. B., Brent, T. P., Mitra, S., Tano, K. Chromosomal localization of human O(6)-methylguanine-DNA methyltransferase (MGMT) gene by in situ hybridization. Mutagenesis 7: 83-85, 1992. [PubMed: 1635460] [Full Text: https://doi.org/10.1093/mutage/7.1.83]
Rydberg, B., Spurr, N., Karran, P. cDNA cloning and chromosomal assignment of the human O(6)-methylguanine-DNA methyltransferase: cDNA expression in Escherichia coli and gene expression in human cells. J. Biol. Chem. 265: 9563-9569, 1990. [PubMed: 2188979]
Smith-Sorensen, B., Lind, G. E., Skotheim, R. I., Fossa, S. D., Fodstad, O., Stenwig, A.-E., Jakobsen, K. S., Lothe, R. A. Frequent promoter hypermethylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene in testicular cancer. Oncogene 21: 8878-8884, 2002. [PubMed: 12483540] [Full Text: https://doi.org/10.1038/sj.onc.1205978]
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J. B., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., Curschmann, J., Janzer, R. C., Ludwin, S. K., Gorlia, T., Allgeier, A., Lacombe, D., Cairncross, J. G., Eisenhauer, E., Mirimanoff, R. O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Eng. J. Med. 352: 987-996, 2005. [PubMed: 15758009] [Full Text: https://doi.org/10.1056/NEJMoa043330]
Tano, K., Shiota, S., Collier, J., Foote, R. S., Mitra, S. Isolation and structural characterization of a cDNA clone encoding the human DNA repair protein for O(6)-alkylguanine. Proc. Nat. Acad. Sci. 87: 686-690, 1990. Note: Erratum: Proc. Nat. Acad. Sci. 87: 3253 only, 1990. [PubMed: 2405387] [Full Text: https://doi.org/10.1073/pnas.87.2.686]
Zunino, A., Arena, G., Rossi, O., Archidiacono, N., Rocchi, M., Romeo, G., Abbondandolo, A. Chromosomal assignment of human O6-methylguanine-DNA-methyltransferase gene by hamster-human somatic cell hybrids. Mutagenesis 6: 395-397, 1991. [PubMed: 1795645] [Full Text: https://doi.org/10.1093/mutage/6.5.395]