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Cancer Causes & Control
Published in: Cancer Causes & Control 2/2011

01-02-2011 | Original paper

MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers

Authors: Kaori Shima, Teppei Morikawa, Yoshifumi Baba, Katsuhiko Nosho, Maiko Suzuki, Mai Yamauchi, Marika Hayashi, Edward Giovannucci, Charles S. Fuchs, Shuji Ogino

Published in: Cancer Causes & Control | Issue 2/2011

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Abstract

Objective

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain.

Methods

Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI).

Results

MGMT hypermethylation was not associated with colorectal cancer–specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.79–1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p = 0.019) and PIK3CA (p = 0.0031).

Conclusions

Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.
Literature
1.
Asaka S, Arai Y, Nishimura Y et al (2009) Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes’ A to Dukes’ B. Carcinogenesis 30:494–499CrossRefPubMed
2.
Gonzalo V, Lozano JJ, Munoz J et al (2010) Aberrant gene promoter methylation associated with sporadic multiple colorectal cancer. PLoS One 5:e8777CrossRefPubMed
3.
Tranah GJ, Bugni J, Giovannucci E et al (2006) O6-methylguanine-DNA methyltransferase Leu84Phe and Ile143Val polymorphisms and risk of colorectal cancer in the nurses’ Health Study and Physicians’ health study (United States). Cancer Causes Control 17:721–731CrossRefPubMed
4.
Zhong Y, Huang Y, Huang Y et al (2010) Effects of O6-methylguanine-DNA methyltransferase (MGMT) polymorphisms on cancer: a meta-analysis. Mutagenesis 25:83–95CrossRefPubMed
5.
Shen L, Kondo Y, Rosner GL et al (2005) MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 97:1330–1338CrossRefPubMed
6.
Nagasaka T, Goel A, Notohara K et al (2008) Methylation pattern of the O6-methylguanine-DNA methyltransferase gene in colon during progressive colorectal tumorigenesis. Int J Cancer 122:2429–2436CrossRefPubMed
7.
Esteller M, Toyota M, Sanchez-Cespedes M et al (2000) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60:2368–2371PubMed
8.
Esteller M, Risques RA, Toyota M et al (2001) Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 61:4689–4692PubMed
9.
Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (2005) O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions. Gut 54:797–802CrossRefPubMed
10.
Ogino S, Kawasaki T, Kirkner GJ et al (2007) Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer. Gut 56:1564–1571CrossRefPubMed
11.
Nosho K, Kawasaki T, Ohnishi M et al (2008) PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia 10:534–541PubMed
12.
Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130CrossRefPubMed
13.
Hegi ME, Sciuscio D, Murat A, Levivier M, Stupp R (2009) Epigenetic deregulation of DNA repair and its potential for therapy. Clin Cancer Res 15:5026–5031CrossRefPubMed
14.
Watson AJ, Sabharwal A, Thorncroft M et al (2010) Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib. Clin Cancer Res 16:743–749CrossRefPubMed
15.
Hegi ME, Liu L, Herman JG et al (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26:4189–4199CrossRefPubMed
16.
van den Bent MJ, Dubbink HJ, Sanson M et al (2009) 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 27:5881–5886CrossRefPubMed
17.
Esteller M, Gaidano G, Goodman SN et al (2002) 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 94:26–32PubMed
18.
Nagasaka T, Sharp GB, Notohara K et al (2003) Hypermethylation of O6-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases. Clin Cancer Res 9:5306–5312PubMed
19.
Krtolica K, Krajnovic M, Usaj-Knezevic S et al (2007) Comethylation of p16 and MGMT genes in colorectal carcinoma: correlation with clinicopathological features and prognostic value. World J Gastroenterol 13:1187–1194PubMed
20.
Chen SP, Chiu SC, Wu CC et al (2009) The association of methylation in the promoter of APC and MGMT and the prognosis of Taiwanese CRC patients. Genet Test Mol Biomarkers 13:67–71CrossRefPubMed
21.
Kim JC, Choi JS, Roh SA et al (2010) Promoter methylation of specific genes is associated with the phenotype and progression of colorectal adenocarcinomas. Ann Surg Oncol 17:1767–1776CrossRefPubMed
22.
Kohonen-Corish MR, Daniel JJ, Chan C et al (2005) Low microsatellite instability is associated with poor prognosis in stage C colon cancer. J Clin Oncol 23:2318–2324CrossRefPubMed
23.
Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142CrossRefPubMed
24.
Ogino S, Kawasaki T, Brahmandam M et al (2005) Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. J Mol Diagn 7:413–421PubMed
25.
Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS (2006) CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn 8:582–588CrossRefPubMed
26.
Ogino S, Brahmandam M, Cantor M et al (2006) Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component. Mod Pathol 19:59–68CrossRefPubMed
27.
Ogino S, Cantor M, Kawasaki T et al (2006) CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 55:1000–1006CrossRefPubMed
28.
Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793CrossRefPubMed
29.
Ogino S, Kawasaki T, Kirkner GJ et al (2007) Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn 9:305–314CrossRefPubMed
30.
Nosho K, Irahara N, Shima K et al (2008) Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One 3:e3698CrossRefPubMed
31.
Ogino S, Kawasaki T, Brahmandam M et al (2006) Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn 8:209–217CrossRefPubMed
32.
Ogino S, Kawasaki T, Nosho K et al (2008) LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int J Cancer 122:2767–2773CrossRefPubMed
33.
Irahara N, Nosho K, Baba Y et al. (2010) Precision of pyrosequencing assay to measure LINE-1 methylation in colon cancer, normal colonic mucosa, and peripheral blood cells. J Mol Diagn 12:177–183
34.
Braun MS, Richman SD, Quirke P et al (2008) Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 26:2690–2698CrossRefPubMed
35.
Weijenberg MP, Luchtenborg M, de Goeij AF et al (2007) Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes. Cancer Causes Control 18:865–879CrossRefPubMed
36.
Samowitz WS, Curtin K, Wolff RK et al (2009) Microsatellite instability and survival in rectal cancer. Cancer Causes Control 20:1763–1768CrossRefPubMed
37.
Berndt SI, Huang WY, Yeager M et al (2009) Genetic variants in frizzled-related protein (FRZB) and the risk of colorectal neoplasia. Cancer Causes Control 20:487–490CrossRefPubMed
38.
Tsilidis KK, Helzlsouer KJ, Smith MW et al (2009) Association of common polymorphisms in IL10, and in other genes related to inflammatory response and obesity with colorectal cancer. Cancer Causes Control 20:1739–1751CrossRefPubMed
39.
Iglesias D, Nejda N, Azcoita MM et al (2009) Effect of COX2–765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer. Cancer Causes Control 20:1421–1429CrossRefPubMed
40.
Figueiredo JC, Levine AJ, Lee WH et al (2009) Genes involved with folate uptake and distribution and their association with colorectal cancer risk. Cancer Causes Control 21:597–608CrossRefPubMed
41.
Van Guelpen B, Dahlin AM, Hultdin J et al (2010) One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study. Cancer Causes Control 21:557–566CrossRefPubMed
42.
Feik E, Baierl A, Hieger B et al (2009) Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk. Cancer Causes Control 21:91–97CrossRefPubMed
43.
Ogino S, Hazra A, Tranah GJ et al (2007) MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis 28:1985–1990CrossRefPubMed
44.
Hawkins NJ, Lee JH, Wong JJ et al (2009) MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa. Mod Pathol 22:1588–1599CrossRefPubMed
45.
Candiloro IL, Dobrovic A (2009) Detection of MGMT promoter methylation in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter single nucleotide polymorphism. Cancer Prev Res (Phila Pa) 2:862–867
46.
Lee BB, Lee EJ, Jung EH et al (2009) Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res 15:6185–6191CrossRefPubMed
47.
Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR (2001) Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 61:827–830PubMed
48.
de Vogel S, Weijenberg MP, Herman JG et al (2009) 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 20:1216–1222CrossRefPubMed
Metadata
Title
MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers
Authors
Kaori Shima
Teppei Morikawa
Yoshifumi Baba
Katsuhiko Nosho
Maiko Suzuki
Mai Yamauchi
Marika Hayashi
Edward Giovannucci
Charles S. Fuchs
Shuji Ogino
Publication date
01-02-2011
Publisher
Springer Netherlands
Published in
Cancer Causes & Control / Issue 2/2011
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI
https://doi.org/10.1007/s10552-010-9698-z

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