Effects of dietary intake and genetic factors on hypermethylation of thehMLH1gene promoter in gastric cancer

Abstract

Abstract Abstract AbstractAIM: Hypermethylation of the promoter of the hMLH1 gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer. METHODS:Data were obtained from a hospital-based, case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age-and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors. Hypermethylation of the hMLH1 gene promoter, polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated. RESULTS:Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene. Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation, whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region. Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53 gene. CONCLUSION:These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1, CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hypermethylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.

Cell proliferation-related genetic polymorphisms and gastric cancer risk: systematic review and meta-analysis

“…Of the four included Asian studies, one showed a significant increase in risk, the other three presented non-significant associations in opposite directions. 39,40,42,45 Diverse results were also found in the two studies involving Caucasians. 43,44 One study on this polymorphism shown in Table 1 was excluded from meta-analysis because the allele frequencies were not reported by the original article.…”

Gene-diet interactions in gastric cancer risk: A systematic review

“…The positive assoc between low fruit or vegetable intake was modified by selected polymorphisms in XRCC1, XPD, MGMT (P interaction = 0.1-0.2) Nan et al [26] ,…”

“…Additionally, Nan et al [26] found that high vegetable intake and low potato intake were associated with an increased risk of gastric cancer caused by hypermethylation of the hMLH1 promoter, which is correlated with the loss of gene expression in South Korea. It is assumed that pickled vegetables are a major source of vegetables in Korean diets; thus, high salt consumption may affect gastric carcinogenesis [27] .…”

Association of the Glutathione S-transferase T1 Null Genotype with Risk of Gastric Cancer: a Meta-analysis in Asian Populations

“…13 articles were excluded after reading the full text. Six were not Asians studies (Gonzalez et al, 2004;Martinez et al, 2006;Ruzzo et al, 2007;Wideroff et al, 2007;Zendehdel et al, 2009;Garcia-Gonzalez et al, 2012), and seven were repeating or overlapping publications (Cai et al, 1999;Setiawan et al, 2001;Gao et al, 2002b;Qian et al, 2003;Sheng et al, 2004;Nan et al, 2005b;Tripathi et al, 2008). Finally, 39 articles that report on the effects of GSTT1 polymorphisms on gastric cancer in Asia covering in total of 7,737 gastric cancer cases and 10,823 controls were remained for data extraction.…”