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

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.