Tumor Biology

, Volume 36, Issue 3, pp 1595–1601 | Cite as

Prognostic value of MGMT methylation in colorectal cancer: a meta-analysis and literature review

  • Yanliang Li
  • Zhongchuan Lyu
  • Lixin Zhao
  • Hong Cheng
  • Dongyuan Zhu
  • Yongsheng Gao
  • Xiuwan Shang
  • Huaijie Shi
Research Article


The development of colorectal cancer (CRC) spans about 5–10 years, making early detection and prevention beneficial to the survival of CRC patients. To address inconsistencies in evidence regarding O 6-methylguanine-DNA-methyltransferase (MGMT) methylation as a potential prognostic factor in CRC, we conducted a meta-analysis to evaluate MGMT methylation in CRC patients. Fourteen studies were included in the meta-analysis after screening 120 articles. The following items were collected from each study: author, published year, country, patient gender, MGMT methylation status, and patients’ disease progression. Pooled hazard ratios and odd ratios with 95 % confidence intervals (CIs) were calculated using fixed or random effect models depending on the heterogeneity between studies. The overall survival of CRC patients was found not to be significantly associated with MGMT methylation. Further subgroup analysis showed that the frequency of MGMT methylation was significantly higher in CRC than in normal tissues (p < 0.00001). MGMT promoter in CRC patients was more frequently methylated than in adenoma patients. In addition, MGMT methylation was significantly increased in adenoma than in normal tissues (p < 0.0001). In conclusion, MGMT methylation is central to the development of cancer that involves a stepwise carcinogenesis of normal adenoma carcinoma cascade. However, MGMT methylation is not associated with the prognosis of CRC.


MGMT Colorectal tumor Diagnosis Prognosis 


Conflicts of interest



  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  2. 2.
    Pegg AE, Dolan ME. Properties and assay of mammalian O 6-alkylguanine-DNA alkyltransferase. Pharmacol Ther. 1987;34:167–79.CrossRefPubMedGoogle Scholar
  3. 3.
    Pegg AE. Mammalian O 6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 1990;50:6119–29.PubMedGoogle Scholar
  4. 4.
    Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4:296–307.CrossRefPubMedGoogle Scholar
  5. 5.
    Ahlquist T, Lind GE, Costa VL, Meling GI, Vatn M, et al. Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers. Mol Cancer. 2008;7:94.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nagasaka T, Goel A, Notohara K, Takahata T, Sasamoto H, et al. Methylation pattern of the O 6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. Int J Cancer. 2008;122:2429–36.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Nilsson TK, Lof-Ohlin ZM, Sun XF. DNA methylation of the p14ARF, RASSF1A and APC1A genes as an independent prognostic factor in colorectal cancer patients. Int J Oncol. 2013;42:127–33.PubMedGoogle Scholar
  8. 8.
    Ishii T, Murakami J, Notohara K, Cullings HM, Sasamoto H, et al. Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa. Gut. 2007;56:13–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Hibi K, Sakata M, Yokomizo K, Kitamura YH, Sakuraba K, et al. Methylation of the MGMT gene is frequently detected in advanced gastric carcinoma. Anticancer Res. 2009;29:5053–5.PubMedGoogle Scholar
  10. 10.
    Ma R, de Pennington N, Hofer M, Blesing C, Stacey R. Diagnostic and prognostic markers in gliomas—an update. Br J Neurosurg. 2013;27:311–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Marucci G, Morandi L, Mazzatenta D, Frank G, Pasquini E, et al. MGMT promoter methylation status in clival chordoma. J Neurooncol. 2014.Google Scholar
  12. 12.
    Coppede F, Migheli F, Lopomo A, Failli A, Legitimo A, et al. Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism. Epigenetics. 2014;9:621–33.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, et al. Methylation tolerance due to an O 6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers. Gut. 2010;59:1516–26.CrossRefPubMedGoogle Scholar
  14. 14.
    Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst. 2005;97:1330–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Kim YH, Petko Z, Dzieciatkowski S, Lin L, Ghiassi M, et al. CpG island methylation of genes accumulates during the adenoma progression step of the multistep pathogenesis of colorectal cancer. Gene Chromosome Cancer. 2006;45:781–9.CrossRefGoogle Scholar
  16. 16.
    Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 2011;8:686–700.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hegi ME, Liu L, Herman JG, Stupp R, Wick W, et al. Correlation of O 6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. 2008;26:4189–99.CrossRefPubMedGoogle Scholar
  18. 18.
    van den Bent MJ, Dubbink HJ, Sanson M, van der Lee-Haarloo CR, Hegi M, et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC brain tumor group study 26951. J Clin Oncol. 2009;27:5881–6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Esteller M, Gaidano G, Goodman SN, Zagonel V, Capello D, et al. Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J Natl Cancer Inst. 2002;94:26–32.CrossRefPubMedGoogle Scholar
  20. 20.
    Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR. Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res. 2001;61:827–30.PubMedGoogle Scholar
  21. 21.
    Brell M, Tortosa A, Verger E, Gil JM, Vinolas N, et al. Prognostic significance of O 6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas. Clin Cancer Res. 2005;11:5167–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Park TJ, Han SU, Cho YK, Paik WK, Kim YB, et al. Methylation of O(6)-methylguanine-DNA methyltransferase gene is associated significantly with K-ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma. Cancer. 2001;92:2760–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Kohonen-Corish MR, Daniel JJ, Chan C, Lin BP, Kwun SY, et al. Low microsatellite instability is associated with poor prognosis in stage C colon cancer. J Clin Oncol. 2005;23:2318–24.CrossRefPubMedGoogle Scholar
  24. 24.
    Shima K, Morikawa T, Baba Y, Nosho K, Suzuki M, et al. MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. Cancer Causes Control. 2011;22:301–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang D, Wang Y, Bai Y, Ge Q, Qiao Y, et al. A novel method to quantify local CpG methylation density by regional methylation elongation assay on microarray. BMC Genomics. 2008;9:59.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Menigatti M, Truninger K, Gebbers JO, Marbet U, Marra G, et al. Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters. Oncogene. 2009;28:899–909.CrossRefPubMedGoogle Scholar
  27. 27.
    Abouzeid HE, Kassem AM, Abdel Wahab AH, El-mezayen HA, Sharad H, et al. Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. Tumour Biol. 2011;32:845–52.CrossRefPubMedGoogle Scholar
  28. 28.
    Chen SP, Chiu SC, Wu CC, Lin SZ, Kang JC, et al. The association of methylation in the promoter of APC and MGMT and the prognosis of Taiwanese CRC patients. Genet Test Mol Biomark. 2009;13:67–71.CrossRefGoogle Scholar
  29. 29.
    Kim JC, Choi JS, Roh SA, Cho DH, Kim TW, et al. Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas. Ann Surg Oncol. 2010;17:1767–76.CrossRefPubMedGoogle Scholar
  30. 30.
    Krtolica K, Krajnovic M, Usaj-Knezevic S, Babic D, Jovanovic D, et al. Comethylation of p16 and MGMT genes in colorectal carcinoma: correlation with clinicopathological features and prognostic value. World J Gastroenterol. 2007;13:1187–94.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lee KH, Lee JS, Nam JH, Choi C, Lee MC, et al. Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence. Langenbecks Arch Surg. 2011;396:1017–26.CrossRefPubMedGoogle Scholar
  32. 32.
    Mokarram P, Zamani M, Kavousipour S, Naghibalhossaini F, Irajie C, et al. Different patterns of DNA methylation of the two distinct O 6-methylguanine-DNA methyltransferase (O 6-MGMT) promoter regions in colorectal cancer. Mol Biol Rep. 2013;40:3851–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Nagasaka T, Sharp GB, Notohara K, Kambara T, Sasamoto H, et al. Hypermethylation of O 6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases. Clin Cancer Res. 2003;9:5306–12.PubMedGoogle Scholar
  34. 34.
    Sinha R, Hussain S, Mehrotra R, Kumar RS, Kumar K, et al. Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation: indicators of tumor staging and metastasis in adenocarcinomatous sporadic colorectal cancer in Indian population. PLoS ONE. 2013;8:e60142.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yanliang Li
    • 1
  • Zhongchuan Lyu
    • 2
  • Lixin Zhao
    • 3
  • Hong Cheng
    • 4
  • Dongyuan Zhu
    • 5
  • Yongsheng Gao
    • 6
  • Xiuwan Shang
    • 7
  • Huaijie Shi
    • 8
    • 9
  1. 1.Department of Gastrointestinal SurgeryShandong Provincial Cancer HospitalJinanChina
  2. 2.Department of Gastrointestinal SurgeryYantai Yuhuangding HospitalYantaiChina
  3. 3.Department of Emergency RadiologyLiaocheng People’s HospitalLiaochengChina
  4. 4.Department of AnesthesiologyJinan Central Hospital Affiliated to Shandong UniversityJinanChina
  5. 5.Department of MedicineShandong Provincial Cancer HospitalJinanChina
  6. 6.Department of PathologyShandong Provincial Cancer HospitalJinanChina
  7. 7.Second Division of General Surgery DepartmentWeihai Wendeng Central HospitalWeihaiChina
  8. 8.First Division of General Surgery DepartmentRizhao City Chinese Medicine HospitalRizhaoChina
  9. 9.Second Division of General Surgery DepartmentWeihai Wendeng Central HospitalWeihaiChina

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