Skip to main content

Advertisement

SpringerLink
Log in

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

  • Original Paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Objectives

Methylenetetrahydrofolate reductase (MTHFR), which is expressed in the liver, may be involved in both DNA methylation and DNA synthesis. It is also indicated as a potential risk factor of liver cancer in patients with chronic liver disease. To date, no study has been conducted on MTHFR and hepatocellular carcinoma (HCC) using a population-based design. The objective of this study was to evaluate the effects of polymorphisms of the MTHFR gene on the risk of primary liver cancer and their possible effect modifications on various environmental risk factors.

Methods

A population-based case–control study was conducted in Taixing, China. MTHFR C677T and A1298C were assayed by PCR-RFLP techniques.

Results

The frequency of MTHFR 677 C/C wild homozygotes genotype was 25.8% in cases, which was lower than that in controls (34.5%). The adjusted odds ratios (ORs) for the MTHFR 677 C/T and T/T genotype were 1.66(95% CI: 1.06–2.61), 1.21(95% CI: 0.65–2.28) respectively when compared with the MTHFR 677 C/C genotype. Subjects carrying any T genotype have the increased risk of 1.55(95% CI: 1.01–2.40) for development of primary hepatocellular carcinoma. A high degree of linkage disequilibrium was observed between the C677T and A1298C polymorphisms, with the D′ of 0.887 and p < 0.01. The MTHFR 677 any T genotype was suggested to have potentially more than multiplicative interactions with raw water drinking with p-value for adjusted interaction of 0.03.

Conclusion

We observed that the MTHFR 677 C/T genotype was associated with an increased risk of primary liver cancer in a Chinese population. The polymorphism of MTHFR 677 might modify the effects of raw water drinking on the risk of primary hepatocellular carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2(9):533–543

    Article  PubMed  CAS  Google Scholar 

  2. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113

    Article  PubMed  CAS  Google Scholar 

  3. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7(2):195–200

    Article  PubMed  CAS  Google Scholar 

  4. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051

    Article  PubMed  Google Scholar 

  5. Ulvik A, Vollset SE, Hansen S, Gislefoss R, Jellum E, Ueland PM (2004) Colorectal cancer and the methylenetetrahydrofolate reductase 677C –> T and methionine synthase 2756A -> G polymorphisms: a study of 2,168 case-control pairs from the JANUS cohort. Cancer Epidemiol Biomarkers Prev 13(12):2175–2180

    PubMed  CAS  Google Scholar 

  6. Yin G, Kono S, Toyomura K, Hagiwara T, Nagano J, Mizoue T, Mibu R, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Yasunami Y, Maekawa T, Takenaka K, Ichimiya H, Imaizumi N (2004) Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci 95(11):908–913

    Article  PubMed  CAS  Google Scholar 

  7. Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willett WC, Hunter DJ (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56(21):4862–4864

    PubMed  CAS  Google Scholar 

  8. Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 8(6):513–518

    PubMed  CAS  Google Scholar 

  9. Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57(6):1098–1102

    PubMed  CAS  Google Scholar 

  10. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96(22):12810–12815

    Article  PubMed  CAS  Google Scholar 

  11. Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF, United Kingdom Childhood Cancer Study investigators (2001) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci USA 98(7):4004–4009

    Article  PubMed  CAS  Google Scholar 

  12. Franco RF, Simoes BP, Tone LG, Gabellini SM, Zago MA, Falcao RP (2001) The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia. Br J Haematol 115(3):616–618

    Article  PubMed  CAS  Google Scholar 

  13. Lin J, Spitz MR, Wang Y, Schabath MB, Gorlov IP, Hernandez LM, Pillow PC, Grossman HB, Wu X (2004) Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study. Carcinogenesis 25(9):1639–1647

    Article  PubMed  CAS  Google Scholar 

  14. Goodman MT, McDuffie K, Hernandez B, Wilkens LR, Bertram CC, Killeen J, Le Marchand L, Selhub J, Murphy S, Donlon TA (2001) Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia. Cancer Epidemiol Biomarkers Prev 10(12):1275–1280

    PubMed  CAS  Google Scholar 

  15. Qi J, Miao XP, Tan W, Yu CY, Liang G, Lu WF, Lin DX (2004) Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of breast cancer. Zhonghua Zhong Liu Za Zhi 26(5):287–289

    PubMed  CAS  Google Scholar 

  16. Beilby J, Ingram D, Hahnel R, Rossi E (2004) Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer 40(8):1250–1254

    Article  PubMed  CAS  Google Scholar 

  17. Song C, Xing D, Tan W, Wei Q, Lin D (2001) Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res 61(8):3272–3275

    PubMed  CAS  Google Scholar 

  18. Shen H, Xu Y, Zheng Y, Qian Y, Yu R, Qin Y, Wang X, Spitz MR, Wei Q (2001) Polymorphisms of 5,10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: a case-control study. Int J Cancer 95(5):332–336

    Article  PubMed  CAS  Google Scholar 

  19. Saffroy R, Pham P, Chiappini F, Gross-Goupil M, Castera L, Azoulay D, Barrier A, Samuel D, Debuire B, Lemoine A (2004) The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis. Carcinogenesis 25(8):1443–1448

    Article  PubMed  CAS  Google Scholar 

  20. Ventura P, Rosa MC, Abbati G, Marchini S, Grandone E, Vergura P, Tremosini S, Zeneroli ML (2005) Hyperhomocysteinaemia in chronic liver diseases: role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics. Liver Int 25(1):49–56

    Article  PubMed  CAS  Google Scholar 

  21. Zoodsma M, Nolte IM, Schipper M, Oosterom E, van der Steege G, de Vries EG, te Meerman GJ, van der Zee AG (2005). Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease. Hum Genet 116(4):247–254

    Article  PubMed  CAS  Google Scholar 

  22. Adinolfi LE, Ingrosso D, Cesaro G, Cimmino A, D’Anto M, Capasso R, Zappia V, Ruggiero G (2005). Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology 41(5):995–1003

    Article  PubMed  CAS  Google Scholar 

  23. Stern LL, Mason JB, Selhub J, Choi SW (2000) Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 9(8):849–853

    PubMed  CAS  Google Scholar 

  24. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64(3):169–172

    Article  PubMed  CAS  Google Scholar 

  25. Miao X, Xing D, Tan W, Qi J, Lu W, Lin D (2002) Susceptibility to gastric cardia adenocarcinoma and genetic polymorphisms in methylenetetrahydrofolate reductase in an at-risk Chinese population. Cancer Epidemiol Biomarkers Prev 11(11):1454–1458

    PubMed  CAS  Google Scholar 

  26. Gao C, Wu J, Ding J, Liu Y, Zang Y, Li S, Su P, Hu X, Xu T, Toshiro T, Kazuo T (2002) Polymorphisms of methylenetetrahydrofolate reductase C677T and the risk of stomach cancer. Zhonghua Liu Xing Bing Xue Za Zhi 23(4):289–292

    PubMed  Google Scholar 

  27. Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R, Fosdick L, Beresford SA, Yasui Y, Potter JD (2000) Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps. Cancer Epidemiol Biomarkers Prev 9(4):427–433

    PubMed  CAS  Google Scholar 

  28. Kureshi N, Ghaffar S, Siddiqui S, Salahuddin I, Frossard PM (2004) Head and neck cancer susceptibility: a genetic marker in the methylenetetrahydrofolate reductase gene. ORL J Otorhinolaryngol Relat Spec 66(5):241–245

    PubMed  CAS  Google Scholar 

  29. Jeng YL, Wu MH, Huang HB, Lin WY, You SL, Chu TY, Chen CJ, Sun CA (2003) The methylenetetrahydrofolate reductase 677C−>T polymorphism and lung cancer risk in a Chinese population. Anticancer Res 23(6D):5149–5152

    PubMed  CAS  Google Scholar 

  30. Gershoni-Baruch R, Dagan E, Israeli D, Kasinetz L, Kadouri E, Friedman E (2000) Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur J Cancer 36(18):2313–2316

    Article  PubMed  CAS  Google Scholar 

  31. Kim DH, Ahn YO, Lee BH, Tsuji E, Kiyohara C, Kono S (2004) Methylenetetrahydrofolate reductase polymorphism, alcohol intake, and risks of colon and rectal cancers in Korea. Cancer Lett 216(2):199–205

    Article  PubMed  CAS  Google Scholar 

  32. Marugame T, Tsuji E, Kiyohara C, Eguchi H, Oda T, Shinchi K, Kono S (2003) Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas. Int J Epidemiol 32(1):64–66

    Article  PubMed  Google Scholar 

  33. Siemianowicz K, Gminski J, Garczorz W, Slabiak N, Goss M, Machalski M, Magiera-Molendowska H (2003) Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer. Oncol Rep 10(5):1341–1344

    PubMed  CAS  Google Scholar 

  34. Bailey LB, Gregory JF 3rd (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129(5):919–922

    PubMed  CAS  Google Scholar 

  35. Laird PW, Jaenisch R (1996) The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet 30:441–464

    Article  PubMed  CAS  Google Scholar 

  36. Siegfried Z, Eden S, Mendelsohn M, Feng X, Tsuberi BZ, Cedar H (1999) DNA methylation represses transcription in vivo. Nat Genet 22(2):203–206

    Article  PubMed  CAS  Google Scholar 

  37. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA 94(7):3290–3295

    Article  PubMed  CAS  Google Scholar 

  38. Solomon E, Borrow J, Goddard AD (1991) Chromosome aberrations and cancer. Sci 254(5035):1153–1160

    Article  CAS  Google Scholar 

  39. Kim YI (2000) Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev 58(7):205–209

    Article  PubMed  CAS  Google Scholar 

  40. Zhang A, Ge XQ (1986) The serum and red cell folate levels in pregnant women in Beijing. Chin Med J (Engl) 99(11):899–902

    CAS  Google Scholar 

  41. Ronnenberg AG, Goldman MB, Aitken IW, Xu X (2000) Anemia and deficiencies of folate and vitamin B-6 are common and vary with season in Chinese women of childbearing age. J Nutr 130(11):2703–2710

    PubMed  CAS  Google Scholar 

  42. Zheng SF, Ershow AG, Yang CS, Li GY, Li RS, Li H, Zou XL, Liu XF, Song LH, Qing QS (1989) Nutritional status in Linxian, China: effects of season and supplementation. Int J Vitam Nutr Res 59(2):190–199

    PubMed  CAS  Google Scholar 

  43. Hao L, Ma J, Stampfer MJ, Ren A, Tian Y, Tang Y, Willett WC, Li Z (2003). Geographical, seasonal and gender differences in folate status among Chinese adults. J Nutr 133(11):3630–3635

    PubMed  CAS  Google Scholar 

  44. Yu SZ, Chen G, Zhi XL, Li J (1998) Primary liver cancer: natural toxins and prevention in China. J Toxicol Sci 23(Suppl 2):143–147

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported in part by the International Union Against Cancer (UICC) Technology Transfer fellowship (ICRETT) awarded to Dr. Li-Na Mu and by the Foundation for the Author of National Excellent Doctoral Dissertation of P.R. China, No. 200157, awarded to Dr. Lin Cai. The study was also partially supported by the NIH National Institute of Environmental Health Sciences, National Cancer Institute, Department of Health and Human Services, Grants ES06718, ES 011667, CA77954, CA09142, CA16042, CA42710, and AT00151, as well as the Alper Research Program of Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center and UCLA Center for Occupational and Environmental Health.

Author information

Authors and Affiliations

  1. Department of Epidemiology, Fudan University School of Public Health, Shanghai, China

    Li-Na Mu, Qing-Wu Jiang, Guo-Rong Wei, Chuan-Wei Chen & Shun-Zhang Yu

  2. Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA, 90095, USA

    Wei Cao, Zuo-Feng Zhang, Nai-Chieh You & Binh Yang Goldstein

  3. Department of Epidemiology, Fujian Medical University, Fuzhou, Fujian, China

    Lin Cai

  4. UCLA Center for Human Nutrition, School of Medicine, Los Angeles, CA, 90095, USA

    Qing-Yi Lu

  5. Taixing Center of Disease Control & Prevention, Taixing, Jiangsu, China

    Xue-Fu Zhou, Bao-Guo Ding & Jun Chang

  6. Department of Epidemiology and Public Health, School of Medicine, Yale University, 60 College Street, LEPH 400, New Haven, CT, 06520-8034, USA

    Li-Na Mu

Authors
  1. Li-Na Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zuo-Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing-Wu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nai-Chieh You
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Binh Yang Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guo-Rong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chuan-Wei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qing-Yi Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xue-Fu Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bao-Guo Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jun Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shun-Zhang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li-Na Mu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mu, LN., Cao, W., Zhang, ZF. et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population. Cancer Causes Control 18, 665–675 (2007). https://doi.org/10.1007/s10552-007-9012-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-007-9012-x

Keywords

Search

Navigation