Risk-Association of DNA Methyltransferases Polymorphisms with Gastric Cancer in the Southern Chinese Population

Abstract

DNA hypomethylation and/or hypermethylation are presumed to be early events in carcinogenesis, and one or more DNA methyltransferases (DNMTs) have been suggested to play roles in carcinogenesis of gastric cancer (GC). However, there have been no systematic studies regarding the association between DNMT gene polymorphisms and GC risk. Here, we examined the associations of 16 single nucleotide polymorphisms (SNPs) from DNMT1 (rs2114724, rs2228611, rs2228612, rs8101866, rs16999593), DNMT2 (rs11695471, rs11254413), DNMT3A (rs1550117, rs11887120, rs13420827, rs13428812, rs6733301), DNMT3B (rs2424908, rs2424913, rs6087990) and DNMT3L (rs113593938) with GC in the Southern Chinese population. We assessed the associations of these 16 SNPs with GC in a case-control study that consisted of 242 GC cases and 294 controls, using the Sequenom MALDI-TOF-MS platform. Association analyses based on the χ2 test and binary logistic regression were performed to determine the odds ratio (OR) and 95% confidence interval (95%CI) for each SNP. We found that rs16999593 in DNMT1, rs11254413 in DNMT2 and rs13420827 in DNMT3A were significantly associated with GC susceptibility (OR 1.45, 0.15, 0.66, respectively; 95% CI 1.00–2.11, p = 0.047; 0.08–0.27, p < 0.01; 0.45–0.97, p = 0.034, respectively, overdominant model). These results suggested that DNMT1, DNMT2 and DNMT3A may play important roles in GC carcinogenesis. However, further studies are required to elucidate the mechanism.

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

“…The relationship between rs36012910 A>G polymorphism and risk of GC, may be due to the linkage disequilibrium with functional polymorphism rs1550117. In Yang's and our studies, no any relationships between rs1550117 with susceptibilities to GC were observed (Yang et al, 2012). Other studies also failed to find significant associations between tag SNPs of DNMT3a and breast cancer risk, or ovarian carcinoma (Mavaddat et al, 2009;Kelemen et al, 2010).…”

“…Several studies have found that DNMT3a is over-expressed in human cancers, suggesting that it may be involved in tumorgenesis and tumor progression (Ding et al, 2008;He et al, 2011;Yang et al, 2011). Recently, DNMT3a SNPs rs1550117 and rs13420827 were also found to be significantly associated with GC (Fan et al, 2010;Wu et al, 2012;Yang et al, 2012). The aim of this study is to confirm the formerly reported association between the DNMT3a polymorphisms and GC in a large number of Chinese subjects, as well as to examine the association with H.pylori infection and GA.…”

“…Other studies also failed to find significant associations between tag SNPs of DNMT3a and breast cancer risk, or ovarian carcinoma (Mavaddat et al, 2009;Kelemen et al, 2010). Although Yang et al examined the associations of 5 SNPs from DNMT3a (rs1550117, rs11887120, rs13420827, rs13428812, rs6733301) with GC in the Southern Chinese population, there was a significant protective effect between GC heterozygosity in rs13420827 and GC in the overdominant model, with OR = 0.66 (0.45-0.97) (Yang et al, 2012). We were unable to find the similar observed association between rs13420827 with risk of GC.…”

“…For example, the rare A allele of the rs1550117 polymorphism in promoter was found to significantly increase DNTM3a transcriptional activity and was associated with an increased risk for GC and colorectal cancer (Fan et al, 2010;Zhao et al, 2012). Moreover, subjects carrying the CG heterozygosity of rs13420827 in 3'UTR was reported with a decreased risk for GC (Yang et al, 2012). However, we did not find any associations between DNMT3a polymorphisms and risk for GA or GC, but the subjects bearing rs1550117 AA genotype had significantly increased a risk of H.pylori infection in our study.…”

“…Several reports indicated that accumulation of aberrant methylation in gastric mucosa produces a field for cancerization, and methylation levels correlate with gastric cancer risk (Guo et al, 2011;Wang et al, 2012). However, few studies have investigated the host factors, such as SNPs of DNA methyltransferases (DNMTs) gene, which may affect epigenetic regulation in gastric mucosa (Fan et al, 2010;Wu et al, 2012;Yang et al, 2012).…”