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01-03-2015 | Research Article

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

Authors: Yanliang Li, Zhongchuan Lyu, Lixin Zhao, Hong Cheng, Dongyuan Zhu, Yongsheng Gao, Xiuwan Shang, Huaijie Shi

Published in: Tumor Biology | Issue 3/2015

Abstract

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.

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.CrossRefPubMed

Pegg AE, Dolan ME. Properties and assay of mammalian O ⁶-alkylguanine-DNA alkyltransferase. Pharmacol Ther. 1987;34:167–79.CrossRefPubMed

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.PubMed

Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4:296–307.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.PubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

11.

Marucci G, Morandi L, Mazzatenta D, Frank G, Pasquini E, et al. MGMT promoter methylation status in clival chordoma. J Neurooncol. 2014.

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

16.

Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 2011;8:686–700.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMedPubMedCentral

Title: Prognostic value of MGMT methylation in colorectal cancer: a meta-analysis and literature review
Authors: Yanliang Li
Zhongchuan Lyu
Lixin Zhao
Hong Cheng
Dongyuan Zhu
Yongsheng Gao
Xiuwan Shang
Huaijie Shi
Publication date: 01-03-2015
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 3/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-014-2752-9

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