Clinical Research Papers:

Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study

Tingting Zhao, Dongying Gu, Zhi Xu, Xinying Huo, Lili Shen, Chun Wang, Yongfei Tang, Peng Wu, Jason He, Weida Gong, Ming-Liang He and Jinfei Chen _

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Oncotarget. 2015; 6:9564-9576. https://doi.org/10.18632/oncotarget.3259

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Tingting Zhao1,5,*, Dongying Gu1,*, Zhi Xu1,*, Xinying Huo1, Lili Shen1, Chun Wang1, Yongfei Tang2, Peng Wu1, Jason He3, Weida Gong4, Ming-Liang He6, Jinfei Chen1,7

1Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

2Department of Surgery, Yixing People’s Hospital, Yixing, China

3College of Letter and Sciences, University of California at Berkeley, CA, USA

4Department of Surgery, Yixing Cancer Hospital, Yixing, China

5Stanley 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

6Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

7Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China

*These authors have contributed equally to this work

Correspondence to:

Jinfei Chen, e-mail: [email protected]

Ming-Liang He, e-mail: [email protected]

Keywords: one-carbon metabolism (OCM), single nucleotide polymorphism (SNP), gastric cancer

Received: December 21, 2014     Accepted: January 31, 2015     Published: March 25, 2015


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.

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