DNMT1 , DNMT3A and DNMT3B Polymorphisms Associated With Gastric Cancer Risk: A Systematic Review and Meta-analysis

Abstract

BackgroundIncreasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease of various tumors. However, the associations between DNMTs variations and gastric cancer (GC) risk were still conflicting. We aimed to assess the effect of DNMTs polymorphisms on the susceptibility to GC.MethodsFirstly, we did a meta-analysis for 7 SNPs (rs16999593, rs2228611, rs8101866 in DNMT1, rs1550117, rs13420827 in DNMT3A, rs1569686, rs2424913 in DNMT3B). Four genetic models (homozygote, heterozygote, dominant and recessive model) were used. Moreover, a meta-sensitivity and subgroup analysis was performed to clarify heterogeneity source. Lastly, 17 SNPs that couldn't be meta-analyzed were presented in a systematic review.Findings20 studies were included, 13 studies could be meta-analyzed and 7 ones could not. Firstly, a meta-analysis on 13 studies (3959 GC cases and 5992 controls) for 7 SNPs showed that GC risk increased in rs16999593 (heterozygote model: OR 1.36, 95%CI 1.14–1.61; dominant model: OR 1.36, 95%CI 1.15–1.60) and rs1550117 (homozygote model: OR 2.03, 95%CI 1.38–3.00; dominant model: OR 1.20, 95%CI 1.01–1.42; recessive model: OR 1.96, 95%CI 1.33–2.89) but decreased in rs1569686 (dominant model: OR 0.74, 95%CI 0.61–0.90). The remaining SNPs were not found associated with GC risk. Furthermore, the subgroup analysis indicated that for rs1550117 and rs1569686, the significant associations were particularly found in people from Chinese Jiangsu province (rs1550117, OR 1.77, 95%CI 1.25–2.51; rs1569686, OR 0.48, 95%CI 0.36–0.64) and that PCR-RFLP was a sensitive method to discover significant associations (rs1550117, OR 1.77, 95%CI 1.25–2.51; rs1569686, OR 0.49, 95%CI 0.37–0.65). Lastly, a systematic review on 7 studies for 17 SNPs suggested that rs36012910, rs7560488 and rs6087990 might have a potential effect on GC initiation.ConclusionThis meta-analysis demonstrated that rs16999593 and rs1550117 could contribute to GC risk and that rs1569686 might be a protective factor against gastric carcinogenesis. By using these SNPs as biomarkers, it is feasible to estimate the risk of acquiring GC and thus formulate timely preventive strategy.

A Single Nucleotide Polymorphism of DNA methyltransferase 3B gene is a risk factor for recurrent spontaneous abortion

“…Although its functionality has not been completely elucidated, three possible mechanisms have been suggested that might affect gene expression, including altered splicing, linkage disequilibrium with other functional polymorphisms and alteration of transcription factor binding affinity . Nevertheless, the DNMT3B rs1569686 polymorphism has been investigated in numerous studies as a potential risk factor for different diseases, including cancer, autoimmune conditions, fertility disorders and pregnancy complications . Although this polymorphism has not been investigated previously in RSA, maternal GG genotype and G allele were detected as risk genotypes for Down syndrome, which is similar to our results .…”

“…In another study, maternal DNMT3B rs1569686‐rs2424913G‐T haplotype also increased the odds for Down syndrome . In contrast to these results, in other diseases, for instance cancer and schizophrenia, the DNMT3B rs1569686 G allele is the protective allele …”

Methylation modification in gastric cancer and approaches to targeted epigenetic therapy (Review)

“…In addition, 23.5% allelic loss of DNMT3A was observed in GC (70). Increment of functional polymorphism of DNMT1, DNMT3A and DNMT3B were found in gastric neoplasm and have been found to be associated with development and progression of GC (65,(71)(72)(73). One meta-analysis showed that DNMT1 rs16999593 and DNMT3A rs1550117 could result in GC and that DNMT3B rs1569686 may be a protective factor against gastric carcinogenesis (73).…”

Exosomal DNMT1 mediates cisplatin resistance in ovarian cancer

“…Inhibition of DNMT1 and HDAC either by knockdown or by pharmaceutical agents in this setting restored the sensitivity of cisplatin. Although it is generally recognized as maintenance apparatus for cellular epigenomic landscape, dysregulated expression or activity of DNMT1 is frequently associated with malignancy transformation . However, the potential link between DNMT1 with drug resistance in ovarian cancer has not been elucidated.…”