Polymorphism of DNA Methyltransferase 3b and Association with Development and Prognosis in Gastric Cancer

Abstract

Objective: DNA methyltransferase 3b (DNMT3b) plays an important role in abnormal methylation during tumorigenesis. Polymorphism of the DNMT3b gene may influence DNMT3b activity and be associated with cancer risk. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) of the DNMT3b gene and susceptibility and prognosis of gastric cancer.

Methods: Four hundred and forty-seven histologically-confirmed gastric cancer cases, 111 gastric atrophy cases and 961 tumor-free controls were enrolled into the study. Five tag SNPs (rs6119954, rs1569686, rs4911107, rs4911259 and rs8118663) of the DNMT3b gene were genotyped by TaqMan assay. DNMT3b expression was evaluated in 104 cancer tissues by immunohistochemistry method.

Results: The median follow-up time for 422 gastric patients with prognosis information was 55.1 (51.8-58.5) month. We found that individuals with the rs1569686 variant genotype (TG/GG) were significantly associated with poor prognosis in gastric cancer compared to those carrying the TT genotype (HR = 1.43, 95%CI: 1.02-1.99). This trend was more evident in the long-term survival of gastric cancer. Similar results were observed for the G allele carriers of rs4911107 and T allele carriers of rs4911259 as these two sites were in complete linkage disequilibrium with rs1569686. The rs8118663 GG carriers tended to live shorter than AA/AG genotype (HR = 2.72, 95%CI: 1.45-5.12) in patients living longer than 2.0 years. None of the five SNPs was associated with the risks of gastric cancer or gastric atrophy. And no relationship was found between each of the five SNPs and DNMT3b expression.

Conclusions: This study provides evidence that DNMT3b polymorphisms may predict long-term survival of gastric cancer. However, further studies are needed to reveal the underlying biological roles of DNMT3b polymorphism.

Fig 1. Survival plots of gastric cancer patients.

(A) plot for rs1569686 using the dominant model (TG/GG vs.TT). Patients carrying rs1569686 TG/GG genotype tended to live shorter than those carrying TT genotype. This trend was more evident in patients who lived longer than 2.0 years with a hazard ratio (HR) 2.46 (95% CI 1.29–4.69) after adjusting for age, sex TNM stage and chemotherapy type. (B) plot for rs8118663 using the recessive model (GG vs. AA/AG). Similar to rs1569686, rs8118663 GG carriers tended to have shorter survival time.