Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia

doi:10.1073/pnas.061408298

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia

Joseph L. Wiemels*,†,‡,
Rosalyn N. Smith*,
G. Malcolm Taylor§,
Osborn B. Eden¶,
Freda E. Alexander‖,
Mel F. Greaves*, and
United Kingdom Childhood Cancer Study Investigators

^*Leukaemia Research Fund Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom; ^†Laboratory for Molecular Epidemiology, Department of Epidemiology and Biostatistics, University of California Medical School, San Francisco, CA 94143-0560; ^§Immunogenetics Laboratory, St. Mary's Hospital, Manchester M13 0JH, United Kingdom; ^¶Academic Unit of Paediatric Oncology, Royal Manchester Children's and Christie Hospital National Health Service Trusts, Withington, Manchester M20 4BX, United Kingdom; and ^‖Department of Public Health Sciences, University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom

Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved January 24, 2001 (received for review August 25, 2000)

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.

Footnotes

↵ ‡ To whom reprint requests should be addressed at: Department of Epidemiology and Biostatistics, 500 Parnassus Avenue, Milberry Union 420-W, University of California, San Francisco, CA 94143-0560. E-mail: jwiemels{at}epi.ucsf.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

NQO1,

NAD(P)H/quinone oxidoreductase;

AdoMet,

S-adenosylmethionine;

MTHFR,

methylenetetrahydrofolate reductase;

THF,

tetrahydrofolate;

C677T,

the T nucleotide variant at nucleotide 677 in MTHFR;

A1298C,

the C variant at nucleotide 1,298 in MTHFR;

ALL,

acute lymphocytic leukemia;

OR,

odds ratio;

CI,

confidence interval