British Journal of Nutrition

Full Papers

Human and Clinical Nutrition

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

Meng-Ying Wua1, Chang-Sheng Kuoa1a2, Ching-Yih Lina3, Chin-Li Lua4 and Rwei-Fen Syu Huanga1 c1

a1 Department of Nutritional Science, Fu Jen University, Hsinchuang, Taiwan, Republic of China

a2 Department of Nutrition, Chi-Mei Medical Centre, Tainan, Taiwan, Republic of China

a3 Section of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Medical Centre, Tainan, Taiwan, Republic of China

a4 Department of Medical Research, Chi-Mei Medical Centre, Tainan, Taiwan, Republic of China

Abstract

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.

(Received October 21 2008)

(Revised January 07 2009)

(Accepted January 09 2009)

(Online publication March 31 2009)

Correspondence:

c1 Corresponding author: Professor Rwei-Fen Syu Huang, fax +886 2 29021215, email 034825@mail.fju.edu.tw

Footnotes

Abbreviations: Ct, threshold cycle number; GOT, glutamate-oxaloacetate transaminase; GPT, glutamate-pyruvate transaminases; HCC, hepatocellular carcinoma; mt, mitochondrial; ROS, reactive oxygen species

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