Advertisement

Tumor Biology

, Volume 36, Issue 8, pp 5839–5848 | Cite as

Clinicopathological significance and potential drug target of O6-methylguanine-DNA methyltransferase in colorectal cancer: a meta-analysis

  • Chen-guo Zheng
  • Chun Jin
  • Le-chi Ye
  • Nian-zhao Chen
  • Zong-Jing Chen
Research Article

Abstract

Emerging evidence indicates that O6-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69–7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC.

Keywords

Colorectal cancer O6-methylguanine-DNA methyltransferase (MGMT) Tumor suppressor gene Methylation Meta-analysis Odds ratio Hazard ratio 

Notes

Conflicts of interest

This work was supported by Wenzhou Municipal Science and Technology Project (Y20090028). The author reports no conflicts of interest in this work.

References

  1. 1.
    Jemal A, Center MM, Desantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev; 2010.Google Scholar
  2. 2.
    Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer. Lancet. 2005;365:153–65.CrossRefPubMedGoogle Scholar
  4. 4.
    McKeown E, Nelson DW, Johnson EK, et al. Current approaches and challenges for monitoring treatment response in colon and rectal cancer. J Cancer. 2014;5:31–43.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ghavifekr Fakhr M, Farshdousti Hagh M, Shanehbandi D, Baradaran B. DNA methylation pattern as important epigenetic criterion in cancer. Genet Res Int. 2013;2013:317569.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Delpu Y, Cordelier P, Cho WC, Torrisani J. DNA methylation and cancer diagnosis. Int J Mol Sci. 2013;14:15029–58.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ma X, Wang YW, Zhang MQ, Gazdar AF. DNA methylation data analysis and its application to cancer research. Epigenomics. 2013;5:301–16.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pegg AE, Dolan ME. Properties and assay of mammalian O6-alkylguanine-DNA alkyltransferase. Pharmacol Ther. 1987;34:167–79.CrossRefPubMedGoogle Scholar
  9. 9.
    Pegg AE. Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 1990;50:6119–29.PubMedGoogle Scholar
  10. 10.
    Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4:296–307.CrossRefPubMedGoogle Scholar
  11. 11.
    Ahlquist T, Lind GE, Costa VL, 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
  12. 12.
    Nagasaka T, Goel A, Notohara K, et al. Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. Int J Cancer. 2008;122:2429–36.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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
  14. 14.
    Kelley GA, Kelley KS. Statistical models for meta-analysis: a brief tutorial. World J Methodol. 2012;2:27–32.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006;11:193–206.CrossRefPubMedGoogle Scholar
  16. 16.
    Reviewer Manager (Rev Man) Copenhagen: The Nordic Cochrane Centre TCC 2008;http://tech.cochrane.org/sites/tech.cochrane.org/files/uploads/documents/revman/RevMan_5.2_User_Guide.pdf.
  17. 17.
    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
  18. 18.
    Nagasaka T, Sharp GB, Notohara K, et al. Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases. Clin Cancer Res. 2003;9:5306–12.PubMedGoogle Scholar
  19. 19.
    Kohonen-Corish MR, Daniel JJ, Chan C, et al. Low microsatellite instability is associated with poor prognosis in stage C colon cancer. J Clin Oncol. 2005;23:2318–24.CrossRefPubMedGoogle Scholar
  20. 20.
    Shen L, Kondo Y, Rosner GL, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst. 2005;97:1330–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Qi J, Zhu YQ, Huang MF, Yang D. Hypermethylation of CpG island in O6-methylguanine-DNA methyltransferase gene was associated with K-ras G to A mutation in colorectal tumor. World J Gastroenterol. 2005;11:2022–5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Krtolica K, Krajnovic M, Usaj-Knezevic S, Babic D, Jovanovic D, Dimitrijevic B. 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
  23. 23.
    Mikami T, Yoshida T, Numata Y, et al. Low frequency of promoter methylation of O6-methylguanine DNA methyltransferase and hMLH1 in ulcerative colitis-associated tumors: comparison with sporadic colonic tumors. Am J Clin Pathol. 2007;127:366–73.CrossRefPubMedGoogle Scholar
  24. 24.
    Menigatti M, Pedroni M, Verrone AM, et al. O6-methylguanine-DNA methyltransferase promoter hypermethylation in colorectal carcinogenesis. Oncol Rep. 2007;17:1421–7.PubMedGoogle Scholar
  25. 25.
    Krakowczyk L, Strzelczyk JK, Adamek B, et al. Methylation of the MGMT and p16 genes in sporadic colorectal carcinoma and corresponding normal colonic mucosa. Med Sci Monit. 2008;14:BR219–25.PubMedGoogle Scholar
  26. 26.
    Chen SP, Chiu SC, Wu CC, et al. The association of methylation in the promoter of APC and MGMT and the prognosis of Taiwanese CRC patients. Genet Test Mol Biomarkers. 2009;13:67–71.CrossRefPubMedGoogle Scholar
  27. 27.
    Hawkins NJ, Lee JH, Wong JJ, Kwok CT, Ward RL, Hitchins MP. MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa. Mod Pathol. 2009;22:1588–99.CrossRefPubMedGoogle Scholar
  28. 28.
    Balic M, Pichler M, Strutz J, et al. High quality assessment of DNA methylation in archival tissues from colorectal cancer patients using quantitative high-resolution melting analysis. J Mol Diagn. 2009;11:102–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    de Vogel S, Weijenberg MP, Herman JG, et al. MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events. Ann Oncol. 2009;20:1216–22.CrossRefPubMedGoogle Scholar
  30. 30.
    Huang CC, Chien WP, Wong RH, Cheng YW, Chen MC, Lee H. NAT2 fast acetylator genotype and MGMT promoter methylation may contribute to gender difference in K-RAS mutation occurrence in Taiwanese colorectal cancer. Environ Mol Mutagen. 2009;50:127–33.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim JC, Choi JS, Roh SA, Cho DH, Kim TW, Kim YS. Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas. Ann Surg Oncol. 2010;17:1767–76.CrossRefPubMedGoogle Scholar
  32. 32.
    Abouzeid HE, Kassem AM, Abdel Wahab AH, El-mezayen HA, Sharad H, Abdel RS. Promoter hypermethylation of RASSF1A, MGMT, and HIC-1 genes in benign and malignant colorectal tumors. Tumour Biol. 2011;32:845–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Lee KH, Lee JS, Nam JH, 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
  34. 34.
    Shima K, Morikawa T, Baba Y, et al. MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. Cancer Causes Control. 2011;22:301–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang D, Wang Y, Bai 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
  36. 36.
    Mokarram P, Zamani M, Kavousipour S, et al. Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer. Mol Biol Rep. 2013;40:3851–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Sinha R, Hussain S, Mehrotra R, 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
  38. 38.
    Li X, Wang Y, Zhang Z, Yao X, Ge J, Zhao Y. Correlation of and methylation levels between peripheral blood leukocytes and colorectal tissue DNA samples in colorectal cancer patients. Oncol Lett. 2013;6:1370–6.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Farzanehfar M, Vossoughinia H, Jabini R, et al. Evaluation of methylation of MGMT (O(6)-methylguanine-DNA methyltransferase) gene promoter in sporadic colorectal cancer. DNA Cell Biol. 2013;32:371–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Wu CC, Kuan JC, Hsu CH, et al. A study of the frequency of methylation of gene promoter regions in colorectal cancer in the Taiwanese population. J Genet. 2013;92:109–13.CrossRefPubMedGoogle Scholar
  41. 41.
    Gao Y, Qu B, Liu B, Ren L. The experimental research of the function of Methyl transferase gene methylation in colorectal tumor. Int J Immun. 2013;36(2):105–13.Google Scholar
  42. 42.
    Ishii T, Murakami J, Notohara K, 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
  43. 43.
    Hibi K, Sakata M, Yokomizo K, et al. Methylation of the MGMT gene is frequently detected in advanced gastric carcinoma. Anticancer Res. 2009;29:5053–5.PubMedGoogle Scholar
  44. 44.
    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
  45. 45.
    Marucci G, Morandi L, Mazzatenta D, Frank G, Pasquini E, Foschini MP. MGMT promoter methylation status in clival chordoma. J Neurooncol. 2014;118(2):271–6. doi: 10.1007/s11060-014-1445-y.Google Scholar
  46. 46.
    Coppede F, Migheli F, Lopomo 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
  47. 47.
    Campan M, Weisenberger DJ, Laird PW. DNA methylation profiles of female steroid hormone-driven human malignancies. Curr Top Microbiol Immunol. 2006;310:141–78.PubMedGoogle Scholar
  48. 48.
    Hegi ME, Liu L, Herman JG, et al. Correlation of O6-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
  49. 49.
    van den Bent MJ, Dubbink HJ, Sanson 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
  50. 50.
    Esteller M, Gaidano G, Goodman SN, 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
  51. 51.
    Brell M, Tortosa A, Verger E, et al. Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas. Clin Cancer Res. 2005;11:5167–74.CrossRefPubMedGoogle Scholar
  52. 52.
    Park TJ, Han SU, Cho YK, Paik WK, Kim YB, Lim IK. 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
  53. 53.
    Ogino S, Hazra A, Tranah GJ, et al. MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis. 2007;28:1985–90.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Chen-guo Zheng
    • 1
  • Chun Jin
    • 1
  • Le-chi Ye
    • 2
  • Nian-zhao Chen
    • 3
  • Zong-Jing Chen
    • 4
  1. 1.Department of ColoproctologyThe Second Affiliated Hospital of Wenzhou Medical UniversityWenzhouPeople’s Republic of China
  2. 2.Department of Oncological SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouPeople’s Republic of China
  3. 3.Department of MedicineThe Chinese Medicine Hospital of WenzhouWenzhouPeople’s Republic of China
  4. 4.Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouPeople’s Republic of China

Personalised recommendations