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

Zhao T, Gu D, Xu Z, Huo X, Shen L, Wang C, Tang Y, Wu P, He J, Gong W, He ML, Chen J - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

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.

No MeSH data available.


Related in: MedlinePlus

The effects of MTRR 66A > G interaction with MTR 2756A > G on survival of gastric cancer patients(A) The effect of MTRR 66A > G interaction with MTR 2756A > G in dominant model on the survival of gastric cancer patients. (B) The effect of MTRR 66A > G interaction with MTR 2756A > G in heterozygote model on the survival of gastric cancer patients.
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Figure 2: The effects of MTRR 66A > G interaction with MTR 2756A > G on survival of gastric cancer patients(A) The effect of MTRR 66A > G interaction with MTR 2756A > G in dominant model on the survival of gastric cancer patients. (B) The effect of MTRR 66A > G interaction with MTR 2756A > G in heterozygote model on the survival of gastric cancer patients.

Mentions: Considering the intricate interactions among the genes described above, we tested polymorphism interactions on the survival of GC patients (Supplementary Table S1–S3). In univariate analysis, MTRR 66 GA + GG genotypes significantly decreased risk of death, but the improved survival disappeared when GC patients simultaneously had MTR 2756 GA + GG genotypes (HR = 1.063, 95% CI = 0.750–1.507, log-rank p = 0.730, Table 4). Interestingly, the protective effect of MTRR 66 GA + GG genotypes was maintained in patients with MTR 2756AA genotypes (HR = 0.720, 95% CI = 0.569–0.910, log-rank p = 0.006). The MTRR 66GA genotype was not associated with the survival of GC patients in univariate analysis, but patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609–0.981, log-rank p = 0.034). However, no significant protective effects were found in patients with MTRR 66GA and MTR 2756GA genotypes (HR = 1.112, 95% CI = 0.764–1.617, log-rank p = 0.580). The effects of MTRR 66A > G interaction with MTR 2756A > G on the survival of GC patients in dominant model and heterozygote model were shown in Figure 2A and Figure 2B.


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

Zhao T, Gu D, Xu Z, Huo X, Shen L, Wang C, Tang Y, Wu P, He J, Gong W, He ML, Chen J - Oncotarget (2015)

The effects of MTRR 66A > G interaction with MTR 2756A > G on survival of gastric cancer patients(A) The effect of MTRR 66A > G interaction with MTR 2756A > G in dominant model on the survival of gastric cancer patients. (B) The effect of MTRR 66A > G interaction with MTR 2756A > G in heterozygote model on the survival of gastric cancer patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496239&req=5

Figure 2: The effects of MTRR 66A > G interaction with MTR 2756A > G on survival of gastric cancer patients(A) The effect of MTRR 66A > G interaction with MTR 2756A > G in dominant model on the survival of gastric cancer patients. (B) The effect of MTRR 66A > G interaction with MTR 2756A > G in heterozygote model on the survival of gastric cancer patients.
Mentions: Considering the intricate interactions among the genes described above, we tested polymorphism interactions on the survival of GC patients (Supplementary Table S1–S3). In univariate analysis, MTRR 66 GA + GG genotypes significantly decreased risk of death, but the improved survival disappeared when GC patients simultaneously had MTR 2756 GA + GG genotypes (HR = 1.063, 95% CI = 0.750–1.507, log-rank p = 0.730, Table 4). Interestingly, the protective effect of MTRR 66 GA + GG genotypes was maintained in patients with MTR 2756AA genotypes (HR = 0.720, 95% CI = 0.569–0.910, log-rank p = 0.006). The MTRR 66GA genotype was not associated with the survival of GC patients in univariate analysis, but patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609–0.981, log-rank p = 0.034). However, no significant protective effects were found in patients with MTRR 66GA and MTR 2756GA genotypes (HR = 1.112, 95% CI = 0.764–1.617, log-rank p = 0.580). The effects of MTRR 66A > G interaction with MTR 2756A > G on the survival of GC patients in dominant model and heterozygote model were shown in Figure 2A and Figure 2B.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

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.

No MeSH data available.


Related in: MedlinePlus