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Interrelationships among genetic C 677 T polymorphism of 5,10‐methylenetetrahydrofolate reductase, biochemical folate status, and lymphocytic p53 oxidative damage in association with tumor malignancy and survivals of patients with hepatocellular carcinoma
Author(s) -
Kuo ChangSheng,
Huang ChiYun,
Kuo HsingTao,
Cheng ChinPao,
Chen ChienHung,
Lu ChinLi,
Yang FeiliLo,
Syu Huang RweiFen
Publication year - 2014
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201200479
Subject(s) - methylenetetrahydrofolate reductase , genotype , reductase , medicine , hepatocellular carcinoma , oxidative stress , biology , oxidative phosphorylation , gastroenterology , genetics , biochemistry , gene , enzyme
Scope Metabolic genotypes of 5,10‐methylenetetrahydrofolate reductase ( MTHFR ) and folate status on oxidative DNA lesions in hepatocellular carcinoma (HCC) has not been elucidated. The aims of the study were to investigate the folate‐polymorphic interactions on genetic oxidative damage in association with advanced HCC malignancy and prognosis. Methods and results The study included 232 HCC patients with folate nutrition, MTHFR C677T polymorphic, p53 genetic and tumour pathological data collected and analyzed for their survivals after a 7.8‐years following up. By adjustment for oxidative risk factors of HCC, the compound CT and TT genotypes in relative to the CC wild‐type were associated with 83% reduced lymphocytic p53 oxidative lesions of HCC patients with RBC folate lower than 688 ng/mL (OR: 0.17, 95%CI: 0.07–0.43). Such genetic protective effects by the CT / TT genotypes were 2‐fold enhanced among those with high RBC folate (OR: 0.08, 95% CI: 0.03–0.21, P for interaction < 0.001). For those with non‐folate‐deficient status, the compound CT and TT vs. CC genotypes were associated with 80% reduced risks of advanced HCC stages (III&IV) (OR: 0.2, 95%CI: 0.08–0.56). Such protection was negated either by adjustment of lymphocytic p53 oxidative lesions or by 3‐fold increased risks among those with high RBC status (OR: 0.6, 95%CI; 0.31–1.41, P for interaction = 0.009). Multivariate Cox proportional hazards analysis showed that the CT / TT genotypes vs. CC wild‐type were the independent predictable factor for better survival outcome of HCC patients (HR: 0.48, CI = 0.30–0.79). For CC homozygote, the second vs. the bottom tertile levels of RBC status were associated with 2‐fold increased mortality rate of HCC patients (HR: 2.05, CI = 1.0–4.1). Conclusion Our data demonstrated that reduced MTHFR activities associated with the MTHFR T allele may interact with RBC folate as the risk modifiers of lymphocytic p53 oxidative lesions of HCC patients. The CT / TT genotypes correlated with lower risks of late‐stage HCC and a favorable survival of HCC patients, depending on p53 oxidative lesions or RBC folate status.