A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma

Abstract

BackgroundDNA-methyltransferase (DNMT)-3A plays an important role in the development of embryogenesis and the generation of aberrant methylation in carcinogenesis. The aim of this study was to investigate the role of a DNMT3A promoter genetic variant on its transcriptional activity and to evaluate the association between DNMT3A gene polymorphism and the susceptibility to gastric cancer (GC) and oesophagus carcinoma (EC) in the Chinese population.MethodsWe selected one of the single nucleotide polymorphisms (SNPs) -448A>G in the DNMT3A promoter region and evaluated its effect on activity using a luciferase assay. -448A>G polymorphisms of DNMT3A were determined by polymerase chain reaction/restriction fragment length polymorphism and confirmed by sequencing. The distribution of -448A>G polymorphisms was detected in 208 GC patients and 346 healthy controls matched for age and gender. The distribution of -448A>G polymorphisms was also detected in 96 EC patients and matched 241 healthy controls. The association of -448A>G polymorphisms of DNMT3A and the risk of GC and EC was evaluated by stratified analysis according to the patient's age and gender.ResultsIn a promoter assay, carriage of the -448 A allele showed a significantly higher promoter activity (> two fold) compared with the -448G allele (P < 0.001). The allele frequency of -448A among GC patients and controls was 32.9% versus 19.9%, respectively. Overall, we found that, compared with GG carriers, the DNMT3A -448AA homozygotes has a > six fold increased risk of GC. Stratification analysis showed that AA homozygotes have a more profound risk in the subgroups of individuals at the age range ≤ 60 years in GC. However, individuals with -448AG and -448AA were not statistically significantly associated with an increased risk of EC compared with those carried the -448GG genotype.ConclusionsThe DNMT3A -448A>G polymorphism is a novel functional SNP and contributes to its genetic susceptibility to GC. -448A>G can be used as a stratification marker to predict an individual's susceptibility to GC, especially in the subgroups of individuals at the age range ≤ 60 years. However, the relative distribution of -448A>G in EC can not be used as a prediction marker in order to evaluate an individual's susceptibility to EC.

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

“…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.…”

“…MUC1 gene expression is regulated by DNA methylation, for instance, MUC1 mRNA expression in MUC1-negative cells was restored by the treatment with (Yamada et al, 2008). The luciferase assay demonstrated that the promoter activity of rs1550117 A allele of DNMT3a was significantly higher (more than two fold) than the G allele in Fan's study (Fan et al, 2010). Therefore, we can propose that DNMT3a rs1550117 GgA transition might increase the expression of DNMT3a and induce transcriptional repression of MUC1, resulting in the attenuation of MUC1 protective function.…”

“…Further studies of DNMT3a sequence variants and their biologic functions may shed light on biological importance of the DNMT3a polymorphism in H.pylori infection. Fan et al (2010) recently found that rs36012910 polymorphism, which located at -2720 bp from the transcription start site in promoter associated with genetic susceptibility to GC (Fan et al, 2010;Wu et al, 2012). However they did not directly confirm that the rs36012910 polymorphism affects the activity of the DNMT3a promoter.…”

“…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).…”

“…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).…”