title: Interrelationships among genetic C677T 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.
abstract: METHODS
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Ph.D. Program in Nutrition and Food Science, Fu Jen Catholic University, HsinChuang, Taiwan.
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Kuo
authors.forename: Chi-Yun
authors.initials: CY
authors.lastname: Huang
authors.forename: Hsing-Tao
authors.initials: HT
authors.lastname: Kuo
authors.forename: Chin-Pao
authors.initials: CP
authors.lastname: Cheng
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Chin-Li
authors.initials: CL
authors.lastname: Lu
authors.forename: Feili-Lo
authors.initials: FL
authors.lastname: Yang
authors.forename: Rwei-Fen
authors.initials: RF
authors.lastname: Syu Huang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004912:Erythrocytes / Q000737:chemistry; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003849:Deoxyguanosine
keywords: Folate status; Hepatocellular carcinoma; MTHFR C677T polymorphism; Oxidative p53 damage; Survival rate