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 extensive promoter methylation (CIMP-low) has not been well-characterised. O-6-methylguanine-DNA methyltransferase (MGMT) acts to repair inappropriately methylated guanine residues in DNA. 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. Materials and methods: Utilizing MethyLight technology, we quantified DNA methylation in MGMT and 8 other markers (a CIMP-diagnostic panel, including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population-based colorectal cancers.
Results: Tumours with both MGMT methylation and loss (assessed by immunohistochemistry) 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 9 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 tumours (33%=52/160, p=0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups.
Conclusion: Relationship between MGMT methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. . Our data also support a molecular difference between MSI-L and MSS in colorectal cancer.
- CpG island methylator phenotype
- colon cancer
- microsatellite instability
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