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Open Access 01-12-2005 | Research article

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

Authors: Eckart Schnakenberg, Andrea Mehles, Gunnar Cario, Klaus Rehe, Kathrin Seidemann, Brigitte Schlegelberger, Holger A Elsner, Karl H Welte, Martin Schrappe, Martin Stanulla

Published in: BMC Medical Genetics | Issue 1/2005

Abstract

Background

Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results.

Methods

We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL.

Results

No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement.

Conclusion

Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population.

Robien K, Ulrich CM: 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol. 2003, 157: 571-582. 10.1093/aje/kwg024.CrossRefPubMed

Kluijtmans LA, Kastelein JJ, Lindemans J, Boers GH, Heil SG, Bruschke AV, Jukema JW, van den Heuvel LP, Trijbels FJ, Boerma GJ, Verheugt FW, Willems F, Blom HJ: Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation. 1997, 96: 2573-2577.CrossRefPubMed

Yamada K, Chen Z, Rozen R, Matthews RG: Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci U S A. 2001, 98: 14853-8. 10.1073/pnas.261469998.CrossRefPubMedPubMedCentral

Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis Ellison R, Eckfeldt JH, Rozen R: The 1298A – >C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis. 2001, 156: 409-15. 10.1016/S0021-9150(00)00671-7.CrossRefPubMed

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995, 10: 111-113. 10.1038/ng0595-111.CrossRefPubMed

Weisberg I, Tran P, Christensen B, Sibani S, Rozen R: A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998, 64: 169-172. 10.1006/mgme.1998.2714.CrossRefPubMed

van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ: A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. Am J Hum Genet. 1998, 62: 1044-1051. 10.1086/301825.CrossRefPubMedPubMedCentral

Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G: Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA. 1999, 96: 12810-12815. 10.1073/pnas.96.22.12810.CrossRefPubMedPubMedCentral

Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J: A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA. 2002, 99: 5606-5611. 10.1073/pnas.062066299.CrossRefPubMedPubMedCentral

10.

Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF, United Kingdom Childhood Cancer Study Investigators: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci USA. 2001, 98: 4004-4009. 10.1073/pnas.061408298.CrossRefPubMedPubMedCentral

11.

Franco RF, Simoes BP, Tone LG, Gabellini SM, Zago MA, Falcao RP: The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukemia. Br J Haematol. 2001, 115: 616-618. 10.1046/j.1365-2141.2001.03140.x.CrossRefPubMed

12.

Matsuo K, Suzuki R, Hamajima N, Ogura M, Kagami Y, Taji H, Kondoh E, Maeda S, Asakura S, Kaba S, Nakamura S, Seto M, Morishima Y, Tajima K: Association between polymorphisms of folate-and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood. 2001, 97: 3205-3209. 10.1182/blood.V97.10.3205.CrossRefPubMed

13.

Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML, Di Bona E, Rodeghiero F, Gilli G, Reverberi R, Caruso A, Pasello M, Pellati A, De Mattei M: Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults. Cancer Epidemiol Biomarkers Prev. 2004, 13: 787-794.PubMed

14.

Lin YW, Aplan PD: Leukemic transformation. Cancer Biol Ther. 2004, 3: 13-20.CrossRefPubMed

15.

Chiusolo P, Reddiconto G, Cimino G, Sica S, Fiorini A, Farina G, Vitale A, Sora F, Laurenti L, Bartolozzi F, Fazi P, Mandelli F, Leone G: Methylenetetrahydrofolate reductase genotypes do not play a role in acute lymphoblastic leukemia pathogenesis in the Italian population. Haematologica. 2004, 89: 139-144.PubMed

16.

Balta G, Yuksek N, Ozyurek E, Ertem U, Hicsonmez G, Altay C, Gurgey A: Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia. Am J Hematol. 2003, 73: 154-160. 10.1002/ajh.10339.CrossRefPubMed

17.

Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Theoret Y, Moghrabi A, Sinnett D: Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood. 2004, 103: 252-257. 10.1182/blood-2003-06-1794.CrossRefPubMed

18.

Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, Gadner H, Odenwald E, Riehm H: Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia. 2000, 14: 2205-2222. 10.1038/sj.leu.2401973.CrossRefPubMed

19.

Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000, 95: 3310-3322.PubMed

20.

Viehmann S, Borkhardt A, Lampert F, Harbott J: Multiplex PCR – a rapid screening method for detection of gene rearrangements in childhood acute lymphoblastic leukemia. Ann Hematol. 1999, 78: 157-162. 10.1007/s002770050494.CrossRefPubMed

21.

Ogino S, Wilson RB: Genotype and haplotype distributions of MTHFR677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis. J Hum Genet. 2003, 48: 1-7. 10.1007/s100380300000.CrossRefPubMed

22.

Labuda D, Krajinovic M, Sabbagh A, Infante-Rivard C, Sinnett D: Parental genotypes in the risk of a complex disease. Am J Hum Genet. 2002, 71: 193-197. 10.1086/341345.CrossRefPubMedPubMedCentral

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/6/23/prepub

Title: Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population
Authors: Eckart Schnakenberg
Andrea Mehles
Gunnar Cario
Klaus Rehe
Kathrin Seidemann
Brigitte Schlegelberger
Holger A Elsner
Karl H Welte
Martin Schrappe
Martin Stanulla
Publication date: 01-12-2005
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2005
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-6-23

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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