Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia
10.1073/pnas.061408298
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
Abstract

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase ( MTHFR ) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL - AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients ( n = 253 total) and healthy newborn controls ( n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C→T) and 1,298 (A→C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations ( MLL +, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15–0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07–0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were observed for hyperdiploid leukemias ( n = 138). No significant associations were evident for either polymorphism with TEL - AML1 + leukemias ( n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

Bibliography

Wiemels, J. L., Smith, R. N., Taylor, G. M., Eden, O. B., Alexander, F. E., & Greaves, M. F. (2001). Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proceedings of the National Academy of Sciences, 98(7), 4004–4009.

Authors 7
  1. Joseph L. Wiemels (first)
  2. Rosalyn N. Smith (additional)
  3. G. Malcolm Taylor (additional)
  4. Osborn B. Eden (additional)
  5. Freda E. Alexander (additional)
  6. Mel F. Greaves (additional)
  7. (additional)
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Dates
Type When
Created 23 years, 1 month ago (July 26, 2002, 10:44 a.m.)
Deposited 3 years, 4 months ago (April 12, 2022, 2:41 p.m.)
Indexed 1 week, 1 day ago (Aug. 28, 2025, 8 a.m.)
Issued 24 years, 5 months ago (March 13, 2001)
Published 24 years, 5 months ago (March 13, 2001)
Published Online 24 years, 5 months ago (March 13, 2001)
Published Print 24 years, 5 months ago (March 27, 2001)
Funders 0

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@article{Wiemels_2001, title={Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia}, volume={98}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.061408298}, DOI={10.1073/pnas.061408298}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Wiemels, Joseph L. and Smith, Rosalyn N. and Taylor, G. Malcolm and Eden, Osborn B. and Alexander, Freda E. and Greaves, Mel F.}, year={2001}, month=mar, pages={4004–4009} }