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

  • Meng-Ying Wu (a1), Chang-Sheng Kuo (a1) (a2), Ching-Yih Lin (a3), Chin-Li Lu (a4) and Rwei-Fen Syu Huang (a1)...

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.

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Corresponding author
*Corresponding author: Professor Rwei-Fen Syu Huang, fax +886 2 29021215, email
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1Amuthan G, Biswas G, Zhang SY, et al. (2001) Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J 20, 19101920.
2Chinnery PF, Samuels DC, Elson J, et al. (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360, 13231325.
3Cloteau DL & Bohr VA (1997) Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem 272, 2540925412.
4Jones JB, Song JJ, Hempen PM, et al. (2001) Detection of mitochondrial DNA mutations in pancreatic cancer offers a ‘mass’-ive advantage over detection of nuclear DNA mutations. Cancer Res 61, 12991304.
5Cortopassi GA, Shibata DD, Soong NW, et al. (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A 89, 73707374.
6Moraes CT, DiMauro S, Zeviani M, et al. (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med 320, 12931299.
7Fliss MS, Usadel H, Caballero OL, et al. (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287, 20172019.
8Polyak K, Li Y, Zhu H, et al. (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20, 291293.
9Ha PK, Tong BC, Westra WH, et al. (2002) Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation. Clin Cancer Res 8, 22602265.
10Jeronimo C, Nomoto S, Caballero OL, et al. (2001) Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene 20, 51955198.
11Yin PH, Lee HC, Chau GY, et al. (2004) Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma. Br J Cancer 90, 23902392.
12Fenech M (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475, 5167.
13Choi SW & Mason JB (2000) Folate and carcinogenesis: an integrated scheme. J Nutr 130, 129132.
14Duthie SJ & Hawdon A (1998) DNA instability strand breakage, uracil misincorporation, and defective repair is increased by folic acid depletion in human lymphocytes in vitro. FASEB J 12, 14911497.
15Duthie SJ, Grant G & Narayanan S (2001) Increased uracil misincorporation in lymphocytes from folate-deficient rats. Br J Cancer 83, 15321537.
16Pogribny IP, Basnakian AG, Miller BJ, et al. (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 55, 18941901.
17Rampersaud GC, Kauwell GP, Hutson AD, et al. (2000) Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr 72, 9981003.
18Branda RF, Brooks EM, Chen Z, et al. (2002) Dietary modulation of mitochondrial DNA deletions and copy number after chemotherapy in rats. Mutat Res 501, 2936.
19Crott JW, Choi SW, Branda RF, et al. (2005) Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutat Res 570, 6370.
20Chou YF, Yu CC & Huang RFS (2007) Changes in mitochondrial (mt) DNA deletion, content and biogenesis in folate-deficient tissues of young rats depend on mt folate and oxidative DNA injuries. J Nutr 100, 596602.
21Ravagnan L, Roumier T & Kroemer G (2002) Mitochondria, the killer organelles and their weapons. J Cell Physiol 192, 131137.
22Parkin DM, Bray F, Ferlay J, et al. (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94, 153156.
23Mikol YB, Hoover KL, Creasia D, et al. (1983) Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 4, 16191629.
24James SJ, Pogribny IP, Pogribna M, et al. (2003) Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J Nutr 133, 3740S3747S.
25Pogribny IP, James SJ, Jernigan S, et al. (2004) Genomic hypomethylation is specific for preneoplastic liver in folate/methyl deficient rats and does not occur in non-target tissues. Mutat Res 548, 5359.
26Welzel TM, Katki HA & Lori C (2007) Blood folate levels and risk of liver damage and hepatocellular carcinoma in a prospective high-risk cohort. Cancer Epidemiol Biomarkers Prev 16, 12791282.
27Varela-Moreiras G & Selhub J (1992) Long-term folate deficiency alters folate content and distribution differentially in rat tissues. J Nutr 122, 986991.
28Horne DW & Patterson D (1988) Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. Clin Chem 34, 23572359.
29He L, Chinnery RF, Durham SE, et al. (2002) Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acid Res 30, 6874.
30Herbert V (1986) The 1986 Herman award lecture. Nutrition science as a continually unfolding story: the folate and vitamin B12 paradigm. Am J Clin Nutr 46, 387402.
31Hagmar L, Bonassi S, Strömberg U, et al. (1998) Chromosomal aberrations in lymphocytes predict human cancer: a report from the European Study Group on Cytogenetic Biomarkers and Health (ESCH). Cancer Res 58, 117121.
32Yamamoto H, Tanaka M, Katayama M, et al. (1992) Significant existence of deleted mitochondrial DNA in cirrhotic liver surrounding hepatic tumor. Biochem Biophys Res Commun 182, 913920.
33Shao JY, Gao HY, Li YH, et al. (2004) Quantitative detection of common deletion of mitochondrial DNA in hepatocellular carcinoma and hepatocellular nodular hyperplasia. World J Gastroenterol 10, 15601564.
34Lezza AM, Boffoli D, Scacco S, et al. (1994) Correlation between mitochondrial DNA 4977-bp deletion and respiratory chain enzyme activities in aging human skeletal muscles. Biochem Biophys Res Commun 205, 772779.
35Wei YH & Lee HC (2002) Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood) 227, 671682.
36Schwarz KB (1996) Oxidative stress during viral infection: a review. Free Radic Biol Med 21, 641649.
37Rezk BM, Haenen GR, van der Vijgh WJ, et al. (2003) Tetrahydrofolate and 5-methyltetrahydrofolate are folates with high antioxidant activity. Identification of the antioxidant pharmacophore. FEBS Lett 555, 601605.
38Doshi SN, McDowell IF, Moat SJ, et al. (2001) Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 21, 11961202.
39Huang RFS, Hsu YC, Lin HL, et al. (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 131, 3338.
40Chang CM, Yu CC, Lu HT, et al. (2007) Folate deprivation promotes mitochondrial oxidative decay: DNA large deletions, cytochrome c oxidase dysfunction, membrane depolarization. Br J Nutr 97, 855863.
41Huang RFS, Yaong HC, Chen SC, et al. (2004) In vitro folate supplementation alleviates oxidative stress, mitochondria-associated death signaling and apoptosis induced by 7-ketocholesterol. Br J Nutr 92, 887894.
42Tarao K, Rino Y, Ohkawa S, et al. (1999) Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis. Cancer (Phila) 86, 589595.
43Tkaczewski W, Niedzielska H, Malafiej E, et al. (1971) Studies of serum folic acid level in patients with viral hepatitis. Polish Med J 10, 10811084.
44Eichner ER & Hillman RS (1971) The evolution of anemia in alcoholic patients. Am J Med 50, 218232.
45Kotake K, Nonami T, Kurokawa T, et al. (1999) Effects of chronic liver diseases on mitochondrial DNA transcription and replication in human liver. Life Sci 65, 557563.
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British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
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