Tingting Zhao¹, Dongying Gu², Jinfei Chen², Zhi Xu², Xinying Huo², Lili Chen², Chun Wang², Yongfei Tang³, Peng Wu², Jason He⁴, Weida Gong⁵, Mingliang He⁶

¹Department of Oncology,Nanjing First Hospital, Nanjing Medical University, ²Nanjing MedicalUniversity, Nanjing First Hospital, ³Department of Surgery,Yixing People's Hospital, ⁴Berkeley, University ofCalifornia, ⁵Department of Surgery,Yixing Cancer Hospital, ⁶Department of BilmedicalScience, City University of HongKong

Objective:Although it has been shown thatpolymorphisms in one-carbon metabolism (OCM) pathway are associated withgastric cancer (GC), their interactions and contributions for patients'survival are elusive. In this study, we investigated the effects ofpolymorphisms and their interactions on the survival of GC patients, includinggenes of Methylenetetrahydrofolatereductase (MTHFR 677C>T,1298A>C), Methioninesynthase reductase (MTRR66A>G), Methionine synthase(MTR 2756A>G), and Thymidylate synthase (TS 3'-UTR ins6 > del6, 5'-UTR 2R>3R).Method: We recruited 919 GC patients from 1998 to 2006. The Kaplan–Meierplots, Cox regression analyses and the log-rank tests were carried out in thisstudy. Result: MTHFR1298CCgenotype showed protective effect (HR=0.444, 95% CI=0.210-0.940). MTRR 66 GA+GG genotypes decreased therisk of death (HR=0.793, 95% CI=0.651-0.967) in general, and in subgroups withmore pronounced diffuse type, greater depth of invasion (T2/T3/T4), higherlevel lymph node metastasis (N1/N2/N3), advanced TNM stages (II/III level) and5-Fu treatment. However, the improved survival disappeared when GC patientssimultaneously had MTR 2756 GA+GG genotypes (HR=1.063, 95% CI=0.750-1.507). Although MTRR 66GA genotype was not associated with the survival of GCpatients, patients with simultaneous MTRR66GA and MTR 2756AA genotypes exhibitedsignificant risk reduction of death (HR=0.773, 95% CI=0.609-0.981). MTHFR 1298 CA + CC combined with TS 5-UTR 2R3R + 3R3Rgenotypes (HR=0.536, 95% CI=0.315-0.913) also increased patient survival rates.Conclusion: Our results suggest that the MTRR 66A>Gand MTHFR 1298A>C polymorphisms may beuseful prognostic biomarkers for GC patients.

Key Words: one-carbonmetabolism (OCM)  single nucleotide polymorphisms