Tumor Biology

, Volume 36, Issue 2, pp 997–1002 | Cite as

Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case–control study

  • Heng Zhang
  • Chunhe Liu
  • Yu-chen Han
  • Zuohong Ma
  • Haiyan Zhang
  • Yinan Ma
  • Xiaofang Liu
Research Article


Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide. However, the exact molecular mechanism of HCC remains uncertain. Many enzymes are involved in one-carbon metabolism (OCM), and single nucleotide polymorphisms (SNPs) in the corresponding genes may play a role in liver carcinogenesis. In this study, we enrolled 1500 HCC patients and 1500 cancer-free controls, which were frequency-matched by age, gender, and HBV infection status. Then eight SNPs from seven OCM genes (MTHFR, MTR, MTRR, FTHFD, GART, SHMT, and CBS) were evaluated. Results showed that six SNPs (MTHFR rs1801133, MTRR rs2287780, MTRR rs10380, FTHFD rs1127717, GART rs8971, and SHMT rs1979277) were significantly associated with HCC risk in Chinese population, with P values range from 2.26 × 10−4 to 0.035). The most significant association was detected for GART rs8971. Compared with individuals with the TT genotype, the age- and sex-adjusted odds ratio (OR) for developing HCC was 1.44 (95 % confidence interval (CI): 1.03–2.02) among those with the CC genotype and 1.30 (95 % CI: 1.10–1.53) for those with CT genotype. Under the log-additive model, each additional copy of minor allele C was associated with a 1.28-fold increased risk of HCC (OR = 1.28, 95 % CI: 1.12–1.45). These findings indicated that genetic variants in OCM genes might contribute to HCC susceptibility.


Polymorphism Hepatocellular carcinoma One-carbon metabolism Genetic Case–control 



We thank all the staffs who were involved in the subject recruitment, telephone interviews, sample preparation, and laboratory assays for their hard works.

Conflicts of interest



  1. 1.
    Yuan JM, Ross RK, Stanczyk FZ, Govindarajan S, Gao YT, Henderson BE, et al. A cohort study of serum testosterone and hepatocellular carcinoma in Shanghai, China. Int J Cancer. 1995;63:491–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang JY, Dai M, Wang X, Lu WQ, Li DS, Zhang MX, et al. A case-control study of hepatitis b and c virus infection as risk factors for hepatocellular carcinoma in Henan, China. Int J Epidemiol. 1998;27:574–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Yu MW, Yang YC, Yang SY, Chang HC, Liaw YF, Lin SM, et al. Androgen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in women. Hepatology. 2002;36:156–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Su H, Zhao J, Xiong Y, Xu T, Zhou F, Yuan Y, et al. Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China. Mutat Res. 2008;641:27–35.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen J, Ma L, Peng NF, Wang SJ, Li LQ. Relationship between GSTT1 gene polymorphism and hepatocellular carcinoma in patients from China. Asian Pac J Cancer Prev. 2012;13:4417–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Zheng J, Li C, Wu X, Yang Y, Hao M, Sheng S, et al. Astrocyte elevated gene-1 is a novel biomarker of epithelial-mesenchymal transition and progression of hepatocellular carcinoma in two China regions. Tumour Biol. 2014;35:2265–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Long XD, Zhao D, Wang C, Huang XY, Yao JG, Ma Y, et al. Genetic polymorphisms in DNA repair genes XRCC4 and XRCC5 and aflatoxin b1-related hepatocellular carcinoma. Epidemiology. 2013;24:671–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Song P. Standardizing management of hepatocellular carcinoma in China: devising evidence-based clinical practice guidelines. Biosci Trends. 2013;7:250–2.PubMedGoogle Scholar
  9. 9.
    Yang D, Hanna DL, Usher J, LoCoco J, Chaudhari P, Lenz HJ, Setiawan VW, El-Khoueiry A. Impact of sex on the survival of patients with hepatocellular carcinoma: a surveillance, epidemiology, and end results analysis. Cancer. 2014. doi: 10.1002/cncr.28912.
  10. 10.
    El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?. Hepatology. 2014Google Scholar
  11. 11.
    Eggert T, McGlynn KA, Duffy A, Manns MP, Greten TF, Altekruse SF. Epidemiology of fibrolamellar hepatocellular carcinoma in the USA, 2000–10. Gut. 2013;62:1667–8.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rustgi VK. Epidemiology of hepatocellular carcinoma. Gastroenterol Clin N Am. 1987;16:545–51.Google Scholar
  13. 13.
    Butler LM, Arning E, Wang R, Bottiglieri T, Govindarajan S, Gao YT, et al. Prediagnostic levels of serum one-carbon metabolites and risk of hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev. 2013;22:1884–93.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wu MY, Kuo CS, Lin CY, Lu CL, Syu Huang RF. Lymphocytic mitochondrial DNA deletions, biochemical folate status and hepatocellular carcinoma susceptibility in a case-control study. Br J Nutr. 2009;102:715–21.CrossRefPubMedGoogle Scholar
  15. 15.
    Rosen MP, Shen S, McCulloch CE, Rinaudo PF, Cedars MI, Dobson AT. Methylenetetrahydrofolate reductase (MTHFR) is associated with ovarian follicular activity. Fertil Steril. 2007;88:632–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Hustad S, Midttun O, Schneede J, Vollset SE, Grotmol T, Ueland PM. The methylenetetrahydrofolate reductase 677c → t polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am J Hum Genet. 2007;80:846–55.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kasap M, Sazci A, Ergul E, Akpinar G. Molecular phylogenetic analysis of methylenetetrahydrofolate reductase family of proteins. Mol Phylogenet Evol. 2007;42:838–46.CrossRefPubMedGoogle Scholar
  18. 18.
    Boccia S, Gianfagna F, Persiani R, La Greca A, Arzani D, Rausei S, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and susceptibility to gastric adenocarcinoma in an Italian population. Biomarkers. 2007;12:635–44.CrossRefPubMedGoogle Scholar
  19. 19.
    Qian X, Lu Z, Tan M, Liu H, Lu D. A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur J Hum Genet. 2007;15:1239–45.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang W, Press OA, Haiman CA, Yang DY, Gordon MA, Fazzone W, et al. Association of methylenetetrahydrofolate reductase gene polymorphisms and sex-specific survival in patients with metastatic colon cancer. J Clin Oncol. 2007;25:3726–31.CrossRefPubMedGoogle Scholar
  21. 21.
    Leclerc D, Rozen R. Endoplasmic reticulum stress increases the expression of methylenetetrahydrofolate reductase through the IRE1 transducer. J Biol Chem. 2008;283:3151–60.CrossRefPubMedGoogle Scholar
  22. 22.
    Toniutto P, Fabris C, Falleti E, Cussigh A, Fontanini E, Bitetto D, et al. Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C. Liver Int. 2008;28:257–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Qi X, Sun X, Xu J, Wang Z, Zhang J, Peng Z. Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk in Chinese population. Tumour Biol. 2014;35:1757–62.CrossRefPubMedGoogle Scholar
  24. 24.
    Mu LN, Cao W, Zhang ZF, Cai L, Jiang QW, You NC, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298c polymorphisms and the risk of primary hepatocellular carcinoma (HCC) in a Chinese population. Cancer Causes Control. 2007;18:665–75.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sun H, Han B, Zhai H, Cheng X, Ma K. Significant association between MTHFR C677T polymorphism and hepatocellular carcinoma risk: a meta-analysis. Tumour Biol. 2014;35:189–93.CrossRefPubMedGoogle Scholar
  26. 26.
    Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, et al. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cbIG complementation group of folate/cobalamin disorders. Hum Mol Genet. 1996;5:1867–74.CrossRefPubMedGoogle Scholar
  27. 27.
    Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci U S A. 1998;95:3059–64.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cheng C, Lingyan W, Yi H, Cheng Z, Huadan Y, Xuting X, et al. Association between TLR2, MTR, MTRR, XPC, TP73, TP53 genetic polymorphisms and gastric cancer: a meta-analysis. Clin Res Hepatol Gastroenterol. 2014;38:346–59.CrossRefPubMedGoogle Scholar
  29. 29.
    Weiner AS, Boyarskikh UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, et al. Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk. Cancer Epidemiol. 2012;36:e95–100.CrossRefPubMedGoogle Scholar
  30. 30.
    Jokic M, Brcic-Kostic K, Stefulj J, Catela Ivkovic T, Bozo L, Gamulin M, et al. Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer. DNA Cell Biol. 2011;30:771–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Wettergren Y, Odin E, Carlsson G, Gustavsson B. MTHFR, MTR, and MTRR polymorphisms in relation to p16INK4A hypermethylation in mucosa of patients with colorectal cancer. Mol Med. 2010;16:425–32.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hu J, Zhou GW, Wang N, Wang YJ. MTRR A66G polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;124:779–84.CrossRefPubMedGoogle Scholar
  33. 33.
    Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Jin F, et al. MTR and MTRR polymorphisms, dietary intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2006;15:586–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Welin M, Grossmann JG, Flodin S, Nyman T, Stenmark P, Tresaugues L, et al. Structural studies of tri-functional human GART. Nucleic Acids Res. 2010;38:7308–19.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wynn SL, Fisher RA, Pagel C, Price M, Liu QY, Khan IM, et al. Organization and conservation of the GART/SON/DONSON locus in mouse and human genomes. Genomics. 2000;68:57–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Brodsky G, Barnes T, Bleskan J, Becker L, Cox M, Patterson D. The human GARS-AIRS-GART gene encodes two proteins which are differentially expressed during human brain development and temporally overexpressed in cerebellum of individuals with down syndrome. Hum Mol Genet. 1997;6:2043–50.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Heng Zhang
    • 1
  • Chunhe Liu
    • 1
  • Yu-chen Han
    • 2
  • Zuohong Ma
    • 3
  • Haiyan Zhang
    • 2
  • Yinan Ma
    • 2
  • Xiaofang Liu
    • 2
  1. 1.China Medical UniversityShenyangChina
  2. 2.Department of Pathology, Basic Science CollegeChina Medical UniversityShenyangChina
  3. 3.Hepatobiliary Pancreatic SurgeryTumor Hospital of Liaoning ProvinceShenyangChina

Personalised recommendations