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Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 4, pages 66–72 (2004)Cite this article

ABSTRACT

The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR)=2.2, 95% confidence interval (CI), 1.0–4.7 and 2.8, 95% CI, 1.1–7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR=2.2, 95% CI, 0.9–5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR=9.0, 95% CI, 1.9–42.8 and 8.9, 95% CI, 1.8–44.6, respectively). These results reveal the role of gene–gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

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Abbreviations

ALL:

acute lymphoblastic leukemia

CML:

chronic myelogenic leukemia

DFS:

disease-free survival

EFS:

event-free survival

10-formyl-THF:

10-formyl tetrahydrofolate

5-methyl-THF:

5-methyltetrahydrofolate

5,10-methylene-THF:

5,10-methylenetetrahydrofolate

MTHFD1:

methylenetetrahydrofolate dehydrogenase

MTHFR:

5,10-methylenetetrahydrofolate reductase

MTX:

methotrexate

NTD:

neural tube defects

OS:

overall survival

WBC:

white blood cell

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Acknowledgements

We are indebted to all patients and their parents who consented to participate in this study. We are grateful to our colleagues Damian Labuda and Daniel Sinnett for discussion and biological material, Mark Bernstein for facilitating access to clinical data and Alan Lovell for critical reading of the manuscript. MK is a scholar of the Fonds de la Recherche en Santé du Québec. EL-B is a recipient of the studentship from the Leukemia Research Funds of Canada. The Canadian Institutes of Health Research, Leukemia Research Fund of Canada and Fondation de l'Hôpital Sainte-Justine supported this study.

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Authors and Affiliations

  1. Centre de Recherche, Hôpital Sainte-Justine,

    M Krajinovic, É Lemieux-Blanchard, S Chiasson, M Primeau, I Costea & A Moghrabi

  2. Centre Hospitalier Universitaire Mère-Enfant, Côte Ste-Catherine, Montréal, Canada

    M Krajinovic, É Lemieux-Blanchard, S Chiasson, M Primeau, I Costea & A Moghrabi

  3. Département de Pédiatrie, Université de Montréal, Québec, Canada

    M Krajinovic & A Moghrabi

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  1. M Krajinovic
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Correspondence to M Krajinovic.

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Krajinovic, M., Lemieux-Blanchard, É., Chiasson, S. et al. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4, 66–72 (2004). https://doi.org/10.1038/sj.tpj.6500224

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