MLH1 promoter methylation frequency in colorectal cancer patients and related clinicopathological and molecular features

PLoS One. 2013;8(3):e59064. doi: 10.1371/journal.pone.0059064. Epub 2013 Mar 29.

Abstract

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • DNA Methylation*
  • Female
  • Humans
  • Male
  • Microsatellite Instability
  • MutL Protein Homolog 1
  • Mutation
  • Neoplasm Grading
  • Neoplasm Staging
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins B-raf / genetics
  • Publication Bias
  • Sex Factors
  • ras Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins B-raf
  • MutL Protein Homolog 1
  • ras Proteins

Grants and funding

This study was supported by grants from National Natural Science Foundation of China for Priority Areas (NSFC 30972538), Education Bureau of Heilongjiang Province (11531100), and the Graduate Foundation, supported by the Scientific Research of Heilongjiang Province (YJSCX2009-224HLJ) and Harbin Medical University (HCXB2009009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.