The Study Between DNA Methyltransferase 1 Gene Polymorphisms And Gastric Cancer Survival

Objective: Gastric cancer(GC) is one of the most common gastrointestinal malignancy and the third leading cause of cancer-related death worldwide.Although radical gastrectomy has been regarded as one of the most effective treatments, the prognosis for GC patients remains poor. In China, the five years survival rate of GC patients is only 27.4%. GC patients have different outcomes even they are at the same environmen exposure, which suggests the genetic factors, play crucial roles in GC prognosis. DNMT1 is the primary enzyme that maintains the level of DNA methylation. Functional disorders of DNMT1 can lead to high methylation suppressor gene inactivation. Aberrant expression of DNMT1 is correlated with progression and prognosis of various cancers. This study chose five tag SNPs in DNMT1 gene to investigate the relationship between the SNP and prognosis of gastric cancer. In order to finding the prognosis markers of gastric cancer and provide reasonable reference basis for individualized treatment.Methods: Genotypes of each SNP were determined by TaqMan SNP genotyping assays in 422 gastric cancer patients. Survival curves of the GC patients within each SNP were plotted by Kaplan-Meier method and compared by log-rank test. The median survival time were estimated by the Kaplan-Meier method. Hazard ratios(HRs) with their 95% confidence intervals(CIs) were calculated by the Cox proportional.Results: The median follow-up time was 54.5 months. Patients with male(P=P=0.044), tumor size>5 cm(P < 0.001), T3/T4(P < 0.001), N1/N2/N3(P <0.001), M1(P < 0.001), TNM III or IV(P < 0.001) and positive for lymph-vascular invasion or neural invasion(P < 0.001) had poor survival.Patients carrying rs2228611 GA/AA genotype tended to live longer than those bearing the GG genotype(P=0.007). After multivariate analysis, patients carrying rs2228611 GA/AA genotype reduced the death risk by 33%(HR=0.67,95% CI=0.51-0.90). Other four SNPs were not associated with the overall survival of GC. Stratified analysis showed that male patients, tumor size>5cm,moderate or well differentiation, positive in lymph-vascular invasion or neural invasion, with radical surgery, no chemotherapy and with relatively early clinical stage reduced the death risk(P < 0.05). Further multivariate Cox regression analysis showed that rs2228611 was an independent predictive factor for GC(GA/AA vs. GG, HR=0.67,95% CI=0.49-0.91), while receiving post-surgery chemotherapy reduced death risk by 31%. While male gender, Ⅲ/Ⅳ stage, tumor size>5cm, with lymph-vascular invasion and receiving palliative surgery increased death risk(P<0.05).Conclusion: Patients carrying rs2228611 GA/AA was an independent protect factor for gastric cancer survival. Patients with chemotherapy after surgery was an independent protect factor for gastric cancer survival. However, male patients, tumor size>5cm, TNM stag≥III, positive in lymph-vascular invasion,with palliative therapy were associated with shorter survival of GC independently. It indicated that we should strengthen the second prevention strategy which include early diagnosis and early treatment for gastric cancer survival.