Consequences of Gene Promoter Hypermethylation in Colorectal Cancer

Background: Promoter hypermethylation of tumour suppressor genes has been established as an important mechanism for gene inactivation. Transcriptional silencing of MGMT by aberrant promoter hypermethylation has been described in a variety of neoplasms, and tumours with high levels of MGMT are likely to be drug-resistant. Promoter hypermethylation of MLH1 has been implicated in a subset of colorectal cancers (CRC) that show microsatellite instability (MSI). We investigated the relationship between MLH1-promoter hypermethylation, MGMT-promoter hypermethylation in a series of colorectal cancers. Design: This study included 110 prospective cases of colorectal cancer. The methylation status of the hMLH1 and MGMT promoters was investigated in each case using methylation-specific PCR. MSI testing was performed using the National Cancer Institute consensus panel of five microsatellite markers. Results were correlated with clinical and pathological features. Results: MGMT-promoter-hypermethylation was detected in 3 of 9 (33%) MSI-H, in 1 of 2 (50%) MSI-L and in 31 of 96 (32%) microsatellite-stable tumours (MSS). MLH1-promoter-hypermethylation was detected in 6 of 9 (66%) MSI-H, in 0 of 2 MSI-L and in 6 of 99 (6%) MSS tumours. Hypermethylation of the MLH1 and MGMT promoters was detected in 18% and 39.5% of cases, respectively. No correlation was detected between hypermethylation of MLH1 or MGMT and tumour site or differentiation. We did observe an inverse correlation between MLH1 and MGMT promoter hypermethylation (p<0.001).