Abstract
This meta-analysis was conducted aiming to evaluate the relationship between abnormal O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and the risk of esophageal cancer (EC). A range of electronic databases was searched: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) without language restrictions. Meta-analysis was performed with the use of the STATA 12.0 software. In the present meta-analysis, 9 clinical cohort studies with a total of 861 EC patients were included. The pooled results revealed that the frequency of MGMT promoter methylation in cancer tissues was significantly higher than in adjacent and normal tissues (cancer tissues vs adjacent tissues, odds ratio (OR) = 6.73, 95 % confidence intervals (95 % CI) 4.75 ~ 9.55, P < 0.001; cancer tissues vs normal tissues, OR = 13.68, 95 % CI 9.47 ~ 19.75, P < 0.001, respectively). Subgroup analyses by pathological type, ethnicity, and sample size suggested that abnormal MGMT promoter methylation also exhibited a higher frequency in all these subgroups (all P < 0.05). Our findings provide empirical evidence that abnormal MGMT promoter methylation may contribute to the risk of EC. Thus, detection of MGMT promoter methylation may be utilized as a valuable diagnostic marker for EC.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs13277-014-2276-3/MediaObjects/13277_2014_2276_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs13277-014-2276-3/MediaObjects/13277_2014_2276_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs13277-014-2276-3/MediaObjects/13277_2014_2276_Fig3_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs13277-014-2276-3/MediaObjects/13277_2014_2276_Fig4_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs13277-014-2276-3/MediaObjects/13277_2014_2276_Fig5_HTML.gif)
Similar content being viewed by others
References
Daly JM, Fry WA, Little AG, Winchester DP, McKee RF, Stewart AK, et al. Esophageal cancer: results of an American college of surgeons patient care evaluation study. J Am Coll Surg. 2000;190(5):562–72. discussion 72-3.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: Globocan 2008. Int J Cancer. 2010;127(12):2893–917.
Wei WQ, Yang J, Zhang SW, Chen WQ, Qiao YL. Analysis of the esophageal cancer mortality in 2004-2005 and its trends during last 30 years in China. Chin J Prev Med. 2010;44(5):398–402.
Hardikar S, Onstad L, Blount PL, Odze RD, Reid BJ, Vaughan TL. The role of tobacco, alcohol, and obesity in neoplastic progression to esophageal adenocarcinoma: a prospective study of barrett's esophagus. PLoS One. 2013;8(1):e52192.
Doecke J, Zhao ZZ, Pandeya N, Sadeghi S, Stark M, Green AC, et al. Polymorphisms in mgmt and DNA repair genes and the risk of esophageal adenocarcinoma. Int J Cancer. 2008;123(1):174–80.
Christmann M, Verbeek B, Roos WP, Kaina B. O(6)-methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry. Biochim Biophys Acta. 2011;1816(2):179–90.
Srivenugopal KS, Ali-Osman F. The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein. Oncogene. 2002;21(38):5940–5.
Huang SH, Lee HS, Mar K, Ji DD, Huang MS, Hsia KT. Loss expression of O6-methylguanine DNA methyltransferase by promoter hypermethylation and its relationship to betel quid chewing in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(6):883–9.
Ma WJ, Lv GD, Zheng ST, Huang CG, Liu Q, Wang X, et al. DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of north xinjiang, china. World J Gastroenterol. 2010;16(5):641–7.
Hasina R, Surati M, Kawada I, Arif Q, Carey GB, Kanteti R, et al. O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer. J Carcinog. 2013;12:20.
Wang J, Sasco AJ, Fu C, Xue H, Guo G, Hua Z, et al. Aberrant DNA methylation of p16, mgmt, and HMLH1 genes in combination with MTHFR C677T genetic polymorphism in esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev. 2008;17(1):118–25.
Baumann S, Keller G, Puhringer F, Napieralski R, Feith M, Langer R, et al. The prognostic impact of o6-methylguanine-DNA methyltransferase (MGMT) promotor hypermethylation in esophageal adenocarcinoma. Int J Cancer. 2006;119(2):264–8.
Hamilton JP, Sato F, Greenwald BD, Suntharalingam M, Krasna MJ, Edelman MJ, et al. Promoter methylation and response to chemotherapy and radiation in esophageal cancer. Clin Gastroenterol Hepatol. 2006;4(6):701–8.
Hochhauser D, Glynne-Jones R, Potter V, Gravalos C, Doyle TJ, Pathiraja K, et al. A phase II study of temozolomide in patients with advanced aerodigestive tract and colorectal cancers and methylation of the O6-methylguanine-DNA methyltransferase promoter. Mol Cancer Ther. 2013;12(5):809–18.
Ling ZQ, Li P, Ge MH, Hu FJ, Fang XH, Dong ZM, et al. Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer. Dig Dis Sci. 2011;56(10):2992–3004.
Stang A. Critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.
Zintzaras E, Ioannidis JP. Hegesma: Genome search meta-analysis and heterogeneity testing. Bioinformatics. 2005;21(18):3672–3.
Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295(6):676–80.
Brock MV, Gou M, Akiyama Y, Muller A, Wu TT, Montgomery E, et al. Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res. 2003;9(8):2912–9.
Fang MZ, ** Z, Wang Y, Liao J, Yang GY, Wang LD, et al. Promoter hypermethylation and inactivation of o(6)-methylguanine-DNA methyltransferase in esophageal squamous cell carcinomas and its reactivation in cell lines. Int J Oncol. 2005;26(3):615–22.
Guo M, Ren J, House MG, Qi Y, Brock MV, Herman JG. Accumulation of promoter methylation suggests epigenetic progression in squamous cell carcinoma of the esophagus. Clin Cancer Res. 2006;12(15):4515–22.
Meng QS, Wang JJ, Li ZF, Kong CB, Cai WJ. Hypermethylation of CpG island in promoter region of DNA repair gene MGMT in esophageal caracinoma. Tumor. 2006;26(8):761–4.
Yang X, Yang SL, Lv QJ, Yan AH. Analysis on the methylation of the promoter of MGMT gene and p16 gene inesophageal squamous cell carcinorma. Carcinogenesis Teratogenesis & Mutagenesis. 2008;20(4):254–7.
Zhang L, Lu W, Miao X, **ng D, Tan W, Lin D. Inactivation of DNA repair gene o6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma. Carcinogenesis. 2003;24(6):1039–44.
Silber JR, Blank A, Bobola MS, Mueller BA, Kolstoe DD, Ojemann GA, et al. Lack of the DNA repair protein o6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors. Proc Natl Acad Sci U S A. 1996;93(14):6941–6.
Dolan ME, Schilsky RL. Silence is golden: gene hypermethylation and survival in large-cell lymphoma. J Natl Cancer Inst. 2002;94(1):6–7.
Nozoe T, Korenaga D, Kabashima A, Sugimachi K. Smoking-related increase of o(6)-methylguanine-DNA methyltransferase expression in squamous cell carcinoma of the esophagus. Cancer Lett. 2002;184(1):49–55.
Christmann M, Tomicic MT, Roos WP, Kaina B. Mechanisms of human DNA repair: An update. Toxicology. 2003;193(1–2):3–34.
Wang L, Zhu D, Zhang C, Mao X, Wang G, Mitra S, et al. Mutations of o6-methylguanine-DNA methyltransferase gene in esophageal cancer tissues from northern china. Int J Cancer. 1997;71(5):719–23.
Crosbie PA, McGown G, Thorncroft MR, O'Donnell PN, Barber PV, Lewis SJ, et al. 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(4):791–5.
Acknowledgments
We would like to acknowledge the helpful comments on this paper received from our reviewers.
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhao, JJ., Li, HY., Wang, D. et al. Abnormal MGMT promoter methylation may contribute to the risk of esophageal cancer: a meta-analysis of cohort studies. Tumor Biol. 35, 10085–10093 (2014). https://doi.org/10.1007/s13277-014-2276-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2276-3