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

• Published in: British journal of nutrition Vol. 102; no. 5; pp. 715 - 721
• Main Authors: Wu, Meng-Ying, Kuo, Chang-Sheng, Lin, Ching-Yih, Lu, Chin-Li, Syu Huang, Rwei-Fen
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 14.09.2009
• Subjects: Aged; Alanine Transaminase; Alanine Transaminase - blood; Alcohol Drinking; Alcohol Drinking - epidemiology; Antigens; Aspartate Aminotransferases; Aspartate Aminotransferases - blood; Biochemical folate status; Biochemistry; Biological and medical sciences; blood; Cancer; Carcinogenesis; Carcinogens; Carcinoma, Hepatocellular; Carcinoma, Hepatocellular - epidemiology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Case studies; Case-Control Studies; Deoxyribonucleic acid; DNA; DNA Primers; DNA Probes; DNA, Mitochondrial; DNA, Mitochondrial - genetics; epidemiology; Feeding. Feeding behavior; Female; Fetuses; Folic acid; Folic Acid - metabolism; Fundamental and applied biological sciences. Psychology; Gene Amplification; Genetic Predisposition to Disease; genetics; Genomic instability; Hepatitis B; Hepatocellular carcinoma; hepatoma; Homocysteine; Hospitals; Human and Clinical Nutrition; Humans; Immunoassay; Laboratories; Liver cancer; liver diseases; Liver injuries; Liver Neoplasms; Liver Neoplasms - epidemiology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; low folate status; Lymphocytes; Lymphocytes - physiology; Magnetic Resonance Imaging; Male; metabolism; Metabolites; Middle Aged; Mitochondrial DNA; Mitochondrial DNA deletions; Modulators; Mutation; nutritional status; Oxidative stress; pathology; patients; physiology; Proteins; Pyruvic acid; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Sequence Deletion; Sex; Smoking; Smoking - epidemiology; Taiwan; Transaminase; Transaminases; Tumors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vitamin B; Vitamin deficiency; Taiwan; United States > US; Hepatocellular carcinoma; Biochemical folate status; Liver injuries; Mitochondrial DNA deletions; Digestive system; Injury; Liver; Hepatic disease; Mitochondrial DNA; Malignant tumor; Case control study; Folic acid; Folate; Vertebrata; Sensitivity; Mammalia; Deletion; Digestive diseases; Lesion; Cancer
• ISSN: 0007-1145; 1475-2662; 1475-2662
• DOI: 10.1017/S0007114509243054

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 α-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 (Δ 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.