Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer

• Published in: Gut 2007-11, Vol.56 (11), p.1564-1571
• Main Authors: Ogino, Shuji, Kawasaki, Takako, Kirkner, Gregory J, Suemoto, Yuko, Meyerhardt, Jeffrey A, Fuchs, Charles S
• Format: Article
• Language: English
• Subjects: Chemotherapy; CIMP; Cohort Studies; colon cancer; Colorectal Cancer; Colorectal Neoplasms - genetics; CpG island methylator phenotype; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA Methylation; Female; Genetic Predisposition to Disease - genetics; Genotype & phenotype; Humans; Immunohistochemistry; Loss of Heterozygosity; Male; Medical personnel; Medical research; MGMT; Microsatellite Instability; Mutation; Nurses; Phenotype; Prospective Studies; Studies; Tumors; Women
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2007.119750

Background:The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer. In contrast, a phenotype with less widespread promoter methylation (CIMP-low) has not been well characterised. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and silencing have been associated with G>A mutations and microsatellite instability-low (MSI-low).Aim:To examine molecular correlates with MGMT methylation/silencing in colorectal cancer.Methods:Utilising MethyLight technology, we quantified DNA methylation in MGMT and eight other markers (a CIMP-diagnostic panel; CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population-based colorectal cancers.Results:Tumours with both MGMT methylation and loss were correlated positively with MSI-low (p = 0.02), CIMP-high (⩾6/8 methylated CIMP markers, p = 0.005), CIMP-low (1/8–5/8 methylated CIMP markers, p = 0.002, compared to CIMP-0 with 0/8 methylated markers), KRAS G>A mutation (p = 0.02), and inversely with 18q loss of heterozygosity (p = 0.0002). Tumours were classified into nine MSI/CIMP subtypes. Among the CIMP-low group, tumours with both MGMT methylation and loss were far more frequent in MSI-low tumours (67%, 12/18) than MSI-high tumours (5.6%, 1/18; p = 0.0003) and microsatellite stable (MSS) tumours (33%, 52/160; p = 0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups.Conclusion:The relationship between MGMT methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting the suggestion that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. Our data support a molecular difference between MSI-low and MSS in colorectal cancer, and a possible link between CIMP-low, MSI-low, MGMT methylation/loss and KRAS mutation.