MLH1 Promoter Methylation Frequency in Colorectal Cancer Patients and Related Clinicopathological and Molecular Features

Purpose: To describe the frequency of MLH1 promoter methylation in colorectal cancer (CRC); to explore the associations between MLH1 promoter methylation and clinicopathological and molecular factors using a systematic review and meta-analysis. Methods: A literature search of the PubMed and Embase databases was conducted to identify relevant articles published up to September 7, 2012 that described the frequency of MLH1 promoter methylation or its associations with clinicopathological and molecular factors in CRC. The pooled frequency, odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. Results: The pooled frequency of MLH1 promoter methylation in unselected CRC was 20.3% (95% CI: 16.8-24.1%). They were 18.7% (95% CI: 14.7-23.6%) and 16.4% (95% CI: 11.9-22.0%) in sporadic and Lynch syndrome (LS) CRC, respectively. Significant associations were observed between MLH1 promoter methylation and gender (pooled OR = 1.641, 95% CI: 1.215-2.215; P = 0.001), tumor location (pooled OR = 3.804, 95% CI: 2.715-5.329; P<0.001), tumor differentiation (pooled OR = 2.131, 95% CI: 1.464-3.102; P<0.001), MSI (OR: 27.096, 95% CI: 13.717-53.526; P<0.001). Significant associations were also observed between MLH1 promoter methylation and MLH1 protein expression, BRAF mutation (OR = 14.919 (95% CI: 6.427-34.631; P<0.001) and 9.419 (95% CI: 2.613-33.953; P = 0.001), respectively). Conclusion: The frequency of MLH1 promoter methylation in unselected CRC was 20.3%. They were 18.7% in sporadic CRC and 16.4% in LS CRC, respectively. MLH1 promoter methylation may be significantly associated with gender, tumor location, tumor differentiation, MSI, MLH1 protein expression, and BRAF mutation.