Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 8/2015

01-08-2015 | Research Article

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

Authors: Chen-guo Zheng, Chun Jin, Le-chi Ye, Nian-zhao Chen, Zong-Jing Chen

Published in: Tumor Biology | Issue 8/2015

Login to get access

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.
Literature
1.
Jemal A, Center MM, Desantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev; 2010.
2.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104–17.CrossRefPubMed
3.
Weitz J, Koch M, Debus J, Hohler T, Galle PR, Buchler MW. Colorectal cancer. Lancet. 2005;365:153–65.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.PubMedPubMedCentral
6.
7.
8.
Pegg AE, Dolan ME. Properties and assay of mammalian O6-alkylguanine-DNA alkyltransferase. Pharmacol Ther. 1987;34:167–79.CrossRefPubMed
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.PubMed
10.
Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4:296–307.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.PubMed
14.
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.CrossRefPubMed
16.
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.PubMed
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
24.
Menigatti M, Pedroni M, Verrone AM, et al. O6-methylguanine-DNA methyltransferase promoter hypermethylation in colorectal carcinogenesis. Oncol Rep. 2007;17:1421–7.PubMed
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.PubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.
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.CrossRefPubMed
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.PubMed
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.CrossRefPubMed
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.
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.CrossRefPubMedPubMedCentral
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.PubMed
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.CrossRefPubMed
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.CrossRefPubMedPubMedCentral
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
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.CrossRefPubMed
Metadata
Title
Clinicopathological significance and potential drug target of O6-methylguanine-DNA methyltransferase in colorectal cancer: a meta-analysis
Authors
Chen-guo Zheng
Chun Jin
Le-chi Ye
Nian-zhao Chen
Zong-Jing Chen
Publication date
01-08-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 8/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3254-0

Other articles of this Issue 8/2015

Tumor Biology 8/2015 Go to the issue

Research Article

Genetic variability of glutathione S-transferases influences treatment outcome of breast cancer

Review

Mitochondrial targeted peptides for cancer therapy

Research Article

Targeting delivery of lipocalin 2-engineered mesenchymal stem cells to colon cancer in order to inhibit liver metastasis in nude mice

Research Article

Downregulation of telomerase activity by diclofenac and curcumin is associated with cell cycle arrest and induction of apoptosis in colon cancer

Research Article

Clinicopathological features of gastric adenocarcinoma patients with metachronous distant metastasis

Research Article

Vitamin D receptor gene polymorphisms and breast cancer risk among postmenopausal Egyptian women
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits