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.

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.

Lymphocytic mitochondrial DNA deletions, biochemical folate status and hepatocellular carcinoma susceptibility in a case-control study.

Mitochondrial (mt) DNA deletions and low folate status, proposed characteristics of carcinogenesis, in relation to human hepatocellular carcinoma (HCC) susceptibility are not clearly understood. We hypothesised that low folate status may modify frequencies of mtDNA deletions in humans, both of which could predispose individuals to HCC development. Biochemical folate status of serum and lymphocytes, and frequencies of mtDNA deletions in lymphocytes were determined in ninety HCC cases and ninety cancer-free healthy controls, individually matched by age and sex. The data revealed that HCC patients had lower levels of serum folate (P = 0.0002), lymphocytic folate (P = 0.040) and accumulated higher frequency of lymphocytic mtDNA deletions (P < 0.0001) than the controls. In the total studied subjects, frequencies of lymphocytic mtDNA deletions were associated with hepatitic B infection (P = 0.004) and HCC incidents (P = 0.001), and were correlated with serum folate (r - 0.155; P = 0.041), lymphocyte folate (r - 0.314; P = 0.0001), levels of glutamate-oxaloacetate transaminase (GOT) (r 0.206; P = 0.006), glutamate-pyruvate transaminase (GPT) (r 0.163; P = 0.037) and alpha-fetal protein concentrations (r 0.212; P = 0.005). After adjustment for age, sex, lifestyle and one-carbon metabolite factors, individuals with low blood folate ( < 11.5 nmol/l) or high mtDNA deletions (Delta threshold cycle number (Ct)>5.3) had increased risks for HCC (OR 7.7, 95 % CI 1.9, 29.9, P = 0.003; OR 5.4; 95 % CI 1.7, 16.8, P = 0.003, respectively). When combined with folate deficiency (serum folate < 14 nmol/l), the OR of HCC in individuals with high levels of lymphocytic mtDNA deletions was enhanced (OR 13.3; 95 % CI 1.45, 122; P = 0.008). Further controlling for GOT and GPT levels, however, negated those effects on HCC risk. Taken together, the data suggest that biochemical folate status and liver injuries are important modulators to lymphocytic mtDNA deletions. The mt genetic instability that results from a high rate of mtDNA deletions and/or low folate status increased the risk for HCC, which is mediated by clinical hepatic lesions.