Association Between hMLH1 Promoter Methylation and Risk of Gastric Cancer: A Meta-Analysis

Abstract

Background: Human mutL homolog 1 (hMLH1) is located on chromosome 3q21-23. As a classic tumor suppressor gene, many researchers have studied the association between hMLH1 promoter methylation and gastric cancer, but their conclusions were not always consistent. Therefore, we performed a meta-analysis to make a more integrated and precise estimate of the associations.Method: PubMed, EMBASE, and Cochrane Library were retrieved without language restrictions. Data were analyzed by Review Manager 5.2 and Stata 12.0 software. Odds ratio (OR) with 95% confidence interval (95%CI) was used to assess the statistical associations.Result: A total of 39 studies published before January 20, 2018 were included in this study. The results indicated that the frequency of hMLH1 promoter methylation in gastric cancers was substantially higher than that in non-cancer controls (OR = 7.94, 95%CI = 4.32–14.58, P < 0.001). Furthermore, hMLH1 promoter methylation had considerable associations with lymph node metastasis, microsatellite instability (MSI), and low expression of hMLH1 protein (OR = 1.53, 95%CI = 1.04–2.26, P = 0.03; OR = 15.33, 95%CI = 9.26–25.36, P < 0.001; OR = 37.86, 95%CI = 18.03–79.50, P < 0.001, respectively). No association was found between hMLH1 promoter methylation and Lauren classification or Helicobacter pylori (HP) infection status.Conclusion: The present study provides evidence that promoter methylation of hMLH1 is a major causative event in the occurrence and development of human gastric cancer.

Molecular Mechanisms Contributing Bacterial Infections to the Incidence of Various Types of Cancer

“…Mutations in hMSH3 and hMSH6 (DNA MMR gene), receptors of growth factors, and transforming growth factor β-RII are seen in MSI-positive gastric carcinoma [60][61][62]. Other DNA MMR gene, hMLH1, and sometimes hMSH2 expression are completely lost [63][64][65][66][67]. These findings are enough to suggest that H. pylori causes deficient MMR in the gastric mucosal cells, resulting in the development of early stages of gastric carcinoma (Table 1).…”

The Pattern of Signatures in Gastric Cancer Prognosis

“…Additionally, MSI tumors alteration status of genes showed common mutations in major histocompatibility complex class I genes, including B2M and HLA-B. To reveal a precise association between human mutL homolog 1 ( hMLH1 ) promoter methylation and gastric cancer, a meta-analysis study was investigated by Ye et al, 2018 [ 34 ]. It was postulated that hMLH1 promoter methylation had significant correlation with not only microsatellite instability, but also with lymph node metastasis and the low expression of hMLH1 protein.…”

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

“…MSI may be related to either inherited or acquired defects in the MMR system, the latter including somatic mutations, deep deletions, or epigenetic silencing [1,25,26]. A meta-analysis of 39 studies (patients n = 4895) highlighted the role of MutL homolog 1 (MLH1) promoter methylation as a founder genetic event in GEC [27]. In this study, the frequency of MLH1 epigenetic silencing was significantly higher in GEC compared to controls (odds ratio (OR) = 7.94; 95% confidence interval (95%CI) = 4.32-14.58; p < 0.001), being closely related to MSI (OR = 15.33; 95%CI = 9.26-25.36; p < 0.001) [27].…”

“…A meta-analysis of 39 studies (patients n = 4895) highlighted the role of MutL homolog 1 (MLH1) promoter methylation as a founder genetic event in GEC [27]. In this study, the frequency of MLH1 epigenetic silencing was significantly higher in GEC compared to controls (odds ratio (OR) = 7.94; 95% confidence interval (95%CI) = 4.32-14.58; p < 0.001), being closely related to MSI (OR = 15.33; 95%CI = 9.26-25.36; p < 0.001) [27]. Furthermore, a meta-analysis involving 48 studies (patients n = 18,612) confirmed that patients with MSI-H GEC (n = 1718; 9.2%) had a significantly better prognosis compared to the microsatellite stable (MSS) counterparts (HR 0.69; 95%CI = 0.56-0.86; p < 0.001) [28].…”