Gastric Cancer Risk And Methylenetetrahydrofolate Reductase Polymorphisms

Background: Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. The mechanism underlying this association might involve genomic instability as a result of insufficient methylation of genomic DNA.. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C→T/Ala222Val and 1298A→C/Glu428Ala) have been described in MTHFR. These variants may be involved in the development of gastric cancer(GC) displaying aberrant DNA methylation and frequently associated with microsatellite instability (MSI).Infection of Helicobacter pylori(H.pylori) is a main risk for development of GC,but the molecular mechanisms of H.pylori-related GC is unknown.Aims: To explore the relationship between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of GC,H.pylori infection or MSI among patients with GC in Chongqing. Methods: Sixty-six patients with GC and 101 control subjects were involved in this study.MTHFR gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)； Helicobacter pylori infection was observed by Warthin-Starry silver staining and PCR, and MSI was detected with polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP).Results: (1). The individuals with 677CT genotype and 677CT+TT genotype group had a 0.21-fold [95% confidence interval(CI),0.43-0.99] and 0.26-fold (95%CI,0.07-0.98) reduced risk of developing gastric cardia cancer compared with those having 677CC genotype. The individuals with 677TT genotype had a 3.63-fold (95%CI,1.04-12.72) increased risk of developing gastric corpus cancer.There was not significant correlation between MTHFR A1298C polymorphisms and the risk of GC.(2) patients with MSI+ GC have an increased frequency of the MTHFR 677TT compared with patients with MSI- GC and control subjects(p＜0.05).There was not significantcorrelation between MTHFR A1298C polymorphisms and MSI.(3) The MSI+ GC was associated with the intestinal type, distal location, larger size, negative lymph node metastases and a earlier stage,suggesting a potential role for MSI as prognostic indicators.(4) There was significantly increased frequency of H.pylori in GC with MSI compared with those in GC without MSI(p＜0.05).Conclusions: (1) The polymorphisms of MTHFR C677T was associated with increased risk for gastric corpus cancer, and was associated with reduced risk for gastric cardia cancer.There was a interaction between MTHFR C677T and MTHFRA128C. The effect of MTHFRA1298C polymorphisms on risk of GC dependeds on the variation of MTHFR C677T polymorphisms. (2) MSI pathway was possibly one of the mechanisms of MTHFR677 polymorphisms adjusting the risk of GC.There was no correlation between MTHFT A1298C and MSI. (3) Tumors with MSI phenotype appear to comprise a biologically and clinically distinct group of GC. MSI+ was associated with favorable prognosis.(4) There was significant correlation between MSI and H.pylori infection,the latter possibly gave rise to GC by MSI pathway. (5) There was no correlation between MTHFR C677T polymorphisms and H.pylori infection.