Biopolym. Cell. 2013; 29(5):367-374.
MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms
1Iatsyshyna A. P., 1Pidpala O. V., 1Lukash L. L.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs) of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the MGMT gene expression and activity of the enzyme. SNPs have been suggested to be the factors which influence the levels of interindividual variability of the MGMT expression. Therefore, the aim of this paper was to review the experimental data on SNPs of the human MGMT gene, which are associated with cancer, as well as on location of MGMT-SNPs in regulatory and protein-coding regions of the gene in relation to its regulation. Lots of MGMT SNPs, which could affect the gene expression and result in interindividual MGMT variability or the enzyme resistance to pseudosubstrate inhibitors, have been re- vealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region. Many of them may have regulatory effect.
Keywords: O6-methylguanine-DNA methyltransferase (MGMT), gene regulation, single nucleotide polymorphism (SNP), transcription factor binding site


[1] Margison G. P., Povey A. C., Kaina B., Santibanez Koref M. F. Variability and regulation of O6-alkylguanine-DNA alkyltransferase Carcinogenesis 2003 24, N 4:625–635.
[2] Kaina B., Christmann M., Naumann S., Roos W. P. MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents DNA Repair (Amst) 2007 6, N 8:1079–1099.
[3] Bugni J. M., Han J., Tsai M. S., Hunter D. J., Samson L. D. Genetic association and functional studies of major polymorphic variants of MGMT DNA Repair (Amst) 2007 6, N 8 P. 1116–1126.
[4] Pegg A. E., Fang Q., Loktionova N. A. Human variants of O6-alkylguanine-DNA alkyltransferase DNA Repair (Amst) 2007 6, N 8:1071–1078.
[5] Margison G. P., Heighway J., Pearson S., McGown G., Thorncroft M. R., Watson A. J., Harrison K. L., Lewis S. J., Rohde K., Barber P. V., O'Donnell P., Povey A. C., Santibanez-Koref M. F. Quantitative trait locus analysis reveals two intragenic sites that influence O6-alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells Carcinogenesis 2005 26, N 8:1473–1480.
[6] Heighway J., Margison G. P., Santibanez-Koref M. F. The alleles of the DNA repair gene O6-alkylguanine-DNA alkyltransferase are expressed at different levels in normal human lung tissue Carcinogenesis 2003 24, N 10:1691–1694.
[7] Stranger B. E., Stahl E. A., Raj T. Progress and promise of genome-wide association studies for human complex trait genetics Genetics 2011 187, N 2:367–383.
[8] Maurano M. T., Humbert R., Rynes E., Thurman R. E., Haugen E., Wang H., Reynolds A.P., Sandstrom R., Qu H., Brody J., Shafer A., Neri F., Lee K., Kutyavin T., Stehling-Sun S., Johnson A. K., Canfield T. K., Giste E., Diegel M., Bates D., Hansen R. S., Neph S., Sabo P. J., Heimfeld S., Raubitschek A., Ziegler S., Cotsapas C., Sotoodehnia N., Glass I., Sunyaev S. R., Kaul R., Stamatoyannopoulos J. A. Systematic localization of common disease-associated variation in regulatory DNA Science 2012 337, N 6099:1190–1195.
[9] Vernot B., Stergachis A. B., Maurano M. T., Vierstra J., Neph S., Thurman R. E., Stamatoyannopoulos J. A., Akey J. M. Personal and population genomics of human regulatory variation Genome Res 2012 22, N 9:1689–1697.
[10] Egyhazi S., Ma S., Smoczynski K., Hansson J., Platz A., Ringborg U. Novel O6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden Hum. Mutat 2002 20, N 5 P. 408–409.
[11] Krzesniak M., Butkiewicz D., Samojedny A., Chorazy M., Rusin M. Polymorphisms in TDG and MGMT genes – epidemiological and functional study in lung cancer patients from Poland Ann. Hum. Genet 2004 68, Pt 4:300–312.
[12] Chae M. H., Jang J. S., Kang H. G., Park J. H., Park J. M., Lee W. K., Kam S., Lee E. B., Son J. W., Park J. Y. O6-AlkylguanineDNA alkyltransferase gene polymorphisms and the risk of primary lung cancer Mol. Carcinog 2006 45, N 4:239–249.
[13] Harris L. C., Potter P. M., Tano K., Shiota S., Mitra S., Brent T. P. Characterization of the promoter region of the human O6methylguanine-DNA methyltransferase gene Nucleic Acids Res 1991 19, N 22:6163–6167.
[14] Benson D. A., Karsch-Mizrachi I., Lipman D. J., Ostell J., Sayers E. W. GenBank Nucleic Acids Res 2011 39, Database issue:D32–D37.
[15] Kent W. J. BLAT – the BLAST-like alignment tool Genome Res 2002 12, N 4:656–664.
[16] Harris L. C., Remack J. S., Brent T. P. Identification of a 59 bp enhancer located at the first exon/intron boundary of the human O6-methylguanine DNA methyltransferase gene Nucleic Acids Res 1994 22, N 22:4614–4619.
[17] Sherry S. T., Ward M. H., Kholodov M., Baker J., Phan L., Smigielski E. M., Sirotkin K. dbSNP: the NCBI database of genetic variation Nucleic Acids Res 2001 29, N 1:308–311.
[18] Meyer L. R., Zweig A. S., Hinrichs A. S., Karolchik D., Kuhn R. M., Wong M., Sloan C. A., Rosenbloom K. R., Roe G., Rhead B., Raney B. J., Pohl A., Malladi V. S., Li C. H., Lee B. T., Learned K., Kirkup V., Hsu F., Heitner S., Harte R. A., Haeussler M., Guruvadoo L., Goldman M., Giardine B. M., Fujita P. A., Dreszer T. R., Diekhans M., Cline M. S., Clawson H., Barber G. P., Haussler D., Kent W. J. The UCSC Genome Browser database: extensions and updates 2013 Nucleic Acids Res 2013 41, Database issue:D64–D69.
[19] Cariaso M., Lennon G. SNPedia: a wiki supporting personal genome annotation, interpretation and analysis Nucleic Acids Res 2012 40, Database issue:D1308–D1312.
[20] Park J. H., Kim N. S., Park J. Y., Chae Y. S., Kim J. G., Sohn S. K., Moon J. H., Kang B. W., Ryoo H. M., Bae S. H., Choi G. S., Jun S. H. MGMT -535G > T polymorphism is associated with prognosis for patients with metastatic colorectal cancer treated with oxaliplatin-based chemotherapy J. Cancer Res. Clin. Oncol 2010 136, N 8:1135–1142.
[21] Ogino S., Hazra A., Tranah G. J., Kirkner G. J., Kawasaki T., Nosho K., Ohnishi M., Suemoto Y., Meyerhardt J. A., Hunter D. J., Fuchs C. S. MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer Carcinogenesis 2007 28, N 9 P. 1985–1990.
[22] Hawkins N. J., Lee J. H., Wong J. J., Kwok C. T., Ward R. L., Hitchins M. P. MGMT methylation is associated primarily with the germline C > T SNP (rs16906252) in colorectal cancer and normal colonic mucosa Mod. Pathol 2009 22, N 12:1588– 1599.
[23] Akbari M. R., Malekzadeh R., Shakeri R., Nasrollahzadeh D., Foumani M., Sun Y., Pourshams A., Sadjadi A., Jafari E., Sotoudeh M., Kamangar F., Boffetta P., Dawsey S. M., Ghadirian P., Narod S. A. Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran Cancer Res 2009 69, N 20:7994–8000.
[24] Doecke J., Zhao Z. Z., Pandeya N., Sadeghi S., Stark M., Green A. C., Hayward N. K., Webb P. M., Whiteman D. C.; Australian Cancer Study. Collaborators (77). Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma Int. J. Cancer 2008 123, N 1:174–180.
[25] Iatsyshyna A. P. MGMT expression: insights into its regulation. Part 1. Epigenetic factors Biopolym. Cell 2013 29, N 2 P. 99–106.
[26] Jones P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond Nat. Rev. Genet 2012 13, N 7 P. 484–492.
[27] Boyle A. P., Hong E. L., Hariharan M., Cheng Y., Schaub M. A., Kasowski M., Karczewski K. J., Park J., Hitz B. C., Weng S., Cherry J. M., Snyder M. Annotation of functional variation in personal genomes using RegulomeDB Genome Res 2012 22, N 9:1790–1797.
[28] Ma S., Egyhazi S., Ueno T., Lindholm C., Kreklau E. L., Stierner U., Ringborg U., Hansson J. O6-methylguanine-DNA-methyltransferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma Br. J. Cancer 2003 89, N 8:1517–1523.
[29] Wang L., Liu H., Zhang Z., Spitz M. R., Wei Q. Association of genetic variants of O6-methylguanine-DNA methyltransferase with risk of lung cancer in non-Hispanic Whites Cancer Epidemiol. Biomarkers Prev 2006 15, N 12:2364–2369.
[30] Imai Y., Oda H., Nakatsuru Y., Ishikawa T. A polymorphism at codon 160 of human O6-methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay Carcinogenesis 1995 16, N 10:2441–2445.
[31] Sylvester R. K., Steen P., Tate J. M., Mehta M., Petrich R. J., Berg A., Kolesar J. Temozolomide-induced severe myelosuppression: analysis of clinically associated polymorphisms in two patients Anticancer Drugs 2011 22, N 1:104–110.
[32] Crosbie P. A., McGown G., Thorncroft M. R., O'Donnell P. N., Barber P. V., Lewis S. J., Harrison K. L., Agius R. M., Santibanez-Koref M. F., Margison G. P., Povey A. C. Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6-alkylguanine-DNA alkyltransferase Int. J. Cancer 2008 122, N 4:791–795.
[33] Hazra A., Chanock S., Giovannucci E., Cox D. G., Niu T., Fuchs C., Willett W. C., Hunter D. J. Large-scale evaluation of genetic variants in candidate genes for colorectal cancer risk in the Nurses' Health Study and the Health Professionals' Follow-up Study Cancer Epidemiol. Biomarkers Prev 2008 17, N 2 P. 311–319.