title: Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study.
abstract: Although it has been shown that polymorphisms in one-carbon metabolism (OCM) pathway are associated with gastric cancer (GC), their interactions and contributions for patients' survival are elusive. In this study, we investigated the effects of polymorphisms and their interactions on the survival of GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR 677C > T, 1298A > C), Methionine synthase reductase (MTRR 66A > G), Methionine synthase (MTR 2756A > G), and Thymidylate synthase (TS 3'-UTR ins6 > del6, 5'-UTR 2R > 3R). We recruited 919 GC patients from 1998 to 2006. The Kaplan-Meier plots, Cox regression analyses and the log-rank tests were carried out in this study. MTHFR 1298CC genotype showed protective effect (HR = 0.444, 95% CI = 0.210-0.940). MTRR 66 GA + GG genotypes decreased the risk of death (HR = 0.793, 95% CI = 0.651-0.967) in general, and in subgroups with more pronounced diffuse type, greater depth of invasion (T2/T3/T4), higher level lymph node metastasis (N1/N2/N3), advanced TNM stages (II/III level) and 5-Fu treatment. However, the improved survival disappeared when GC patients simultaneously 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 GC patients, patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609-0.981). MTHFR 1298 CA + CC combined with TS 5-UTR 2R3R + 3R3R genotypes (HR = 0.536, 95% CI = 0.315-0.913) also increased patient survival rates. Our results suggest that the MTRR 66A > G and MTHFR 1298A > C polymorphisms may be useful prognostic biomarkers for GC patients.
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.|Stanley Ho Center for Emerging Infectious Diseases, and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Dongying
authors.initials: D
authors.lastname: Gu
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Surgery, Yixing People's Hospital, Yixing, China.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: College of Letters and Science, University of California at Berkeley, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Surgery, Yixing Cancer Hospital, Yixing, China.
authors.forename: Weida
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.|Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Chen
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D019875:One-Carbon Group Transferases / Q000235:genetics*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013940:Thymidylate Synthase / Q000235:genetics; D047368:Tumor Burden
chemical_list: D020121:5' Untranslated Regions; D009363:Neoplasm Proteins; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D019875:One-Carbon Group Transferases; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase
keywords: gastric cancer; one-carbon metabolism (OCM); single nucleotide polymorphism (SNP)
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