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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

Overall survival of MTRR 66A > G dominant genotypes in gastric cancer patients
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Figure 1: Overall survival of MTRR 66A > G dominant genotypes in gastric cancer patients

Mentions: The relationships between individual polymorphisms and survival of GC patients in different genetic models were assessed by Cox regression analyses. Codominant, dominant and recessive models were applied in this study (Table 2). We first observed that MTRR 66GG genotype significantly protected GC patients from death. The MST of patients with GG genotype was extended from 51 to 87 months (HR = 0.500, 95% CI = 0.291–0.856, p = 0.014) when compared to those with AA genotype. A similar result was also obtained in a recessive model (HR = 0.537, 95% CI = 0.315–0.915, p = 0.019). Further analysis of MTRR 66A > G polymorphism in the dominant model revealed a remarkably longer survival time in GC patients (MST, 97.0 months; HR = 0.793, 95% CI = 0.651–0.967, p = 0.022) as compared to that in AA homozygote (Table 2). The overall survival of GC patients with 66A > G dominant genotypes (AG + GG) was presented in Figure 1. Heterozygote 66A > G genotypes exhibited marginal prolongation of survival of GC patients (HR = 0.883, 95% CI = 0.684–1.028, Table 2).


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)

Overall survival of MTRR 66A > G dominant genotypes in gastric cancer patients
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Overall survival of MTRR 66A > G dominant genotypes in gastric cancer patients
Mentions: The relationships between individual polymorphisms and survival of GC patients in different genetic models were assessed by Cox regression analyses. Codominant, dominant and recessive models were applied in this study (Table 2). We first observed that MTRR 66GG genotype significantly protected GC patients from death. The MST of patients with GG genotype was extended from 51 to 87 months (HR = 0.500, 95% CI = 0.291–0.856, p = 0.014) when compared to those with AA genotype. A similar result was also obtained in a recessive model (HR = 0.537, 95% CI = 0.315–0.915, p = 0.019). Further analysis of MTRR 66A > G polymorphism in the dominant model revealed a remarkably longer survival time in GC patients (MST, 97.0 months; HR = 0.793, 95% CI = 0.651–0.967, p = 0.022) as compared to that in AA homozygote (Table 2). The overall survival of GC patients with 66A > G dominant genotypes (AG + GG) was presented in Figure 1. Heterozygote 66A > G genotypes exhibited marginal prolongation of survival of GC patients (HR = 0.883, 95% CI = 0.684–1.028, Table 2).

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