Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Reduced folate carrier and methylenetetrahydrofolate reductase gene polymorphisms: associations with clinical outcome in childhood acute lymphoblastic leukemia

Leukemia volume 23, pages 1348–1351 (2009)Cite this article

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed during childhood. Although the 5-year survival rate of children treated for ALL is now above 80%, a considerable proportion of these children continue to relapse or die during or after completing therapy. The anti-folate cancer drug, methotrexate (MTX), is a critical component of ALL chemotherapy protocols and poor cellular response to MTX can substantially contribute to treatment failure in children treated for ALL.1 Moreover, recent studies have also provided evidence suggesting that common polymorphisms in genes of the folate pathway may play an important role in determining treatment efficacy and toxicity in patients treated for ALL.2, 3, 4

Two common polymorphisms have been extensively described in the MTHFR gene. The first polymorphism, MTHFR C677T, involves a C to T transition causing an alanine to valine substitution at amino acid position 222, whereas the second, MTHFR A1298C, involves an A to C transversion causing a glutamic acid to alanine replacement at amino acid position 429. Both of these variants have been shown to have an impact on enzyme activity. Earlier studies have shown enzymatic activity to be reduced by up to 60% in individuals homozygous for MTHFR 677TT and to a lesser extent in those heterozygous for MTHFR 677TC, whereas other studies have shown that the MTHFR 1298C polymorphism results in decreased enzyme activity in vitro, although not to the levels observed in carriers of the MTHFR 677T polymorphism (reviewed by Schwahn and Rozen5). Investigators have also reported an increased frequency of MTHFR 677TT homozygosity in leukaemia patients intolerant to MTX, suggesting that the MTHFR 677TT polymorphism is associated with increased MTX toxicity or reduced survival, owing to interference with MTX activity.3, 5

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Kager L, Cheok M, Yang W, Zaza G, Cheng Q, Panetta JC et al. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest 2005; 115: 110–116.

    Article  CAS  Google Scholar 

  2. Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M . Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate levels and outcome of childhood acute lymphoblastic leukemia. Blood 2002; 100: 3832–3834.

    Article  Google Scholar 

  3. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A . Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 2004; 4: 66–72.

    Article  CAS  Google Scholar 

  4. Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 2005; 105: 4752–4758.

    Article  CAS  Google Scholar 

  5. Schwahn B, Rozen R . Polymorphisms in the methylenetetrahydrofolate reductase gene. Clinical consequences. Am J Pharmacogenomics 2001; 1: 189–201.

    Article  CAS  Google Scholar 

  6. Chango A, Emery-Fillon N, Potier de Courcy G, Lambert D, Pfister M, Rosenblatt DS et al. A polymorphism (80G → A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab 2000; 70: 310–315.

    Article  CAS  Google Scholar 

  7. Whetstine JW, Gifford AJ, Witt T, Liu XY, Flatley RM, Norris M et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high frequency G/A variant at position 80 and transport properties of the His27 and Arg27 carriers. Clin Cancer Res 2001; 7: 3416–3422.

    CAS  PubMed  Google Scholar 

  8. Gast A, Bermejo JL, Flohr T, Stanulla M, Burwinkel B, Schrappe M et al. Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case–control study. Leukemia 2007; 21: 320–325.

    Article  CAS  Google Scholar 

  9. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M et al. Polyglutamylation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2766–2774.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. This work was supported by grants from the National Health and Medical Research Council (Australia) (MDN, MH) and the New South Wales Cancer Council (Australia) (MDN, MH).

Author information

Author notes

  1. L J Ashton and A J Gifford: These authors contributed equally to this study.

Authors and Affiliations

  1. Molecular Epidemiology Group, Children's Cancer Institute Australia for Medical Research, Randwick, Australia

    L J Ashton & D T T Lau

  2. Molecular Diagnostics Program, Children's Cancer Institute Australia for Medical Research, Randwick, Australia

    A J Gifford, E Kwan, A Lingwood & M D Norris

  3. Molecular Carcinogenesis Program, Children's Cancer Institute Australia for Medical Research, Randwick, Australia

    G M Marshall

  4. Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, Australia

    G M Marshall

  5. Experimental Therapeutics Program, Children's Cancer Institute Australia for Medical Research, Randwick, Australia

    M Haber

Authors
  1. L J Ashton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A J Gifford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Kwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Lingwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D T T Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G M Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M D Norris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L J Ashton.

Additional information

Supplementary information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ashton, L., Gifford, A., Kwan, E. et al. Reduced folate carrier and methylenetetrahydrofolate reductase gene polymorphisms: associations with clinical outcome in childhood acute lymphoblastic leukemia. Leukemia 23, 1348–1351 (2009). https://doi.org/10.1038/leu.2009.67

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.67

This article is cited by

Search

Advanced search

Quick links