Annals of Hematology

, 85:291 | Cite as

MTHFR 677 (C→T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95

  • Kathrin Seidemann
  • Marion Book
  • Martin Zimmermann
  • Ulrike Meyer
  • Karl Welte
  • Martin Stanulla
  • Alfred Reiter
Original Article


We analyzed the relationship of genetic variation within the methylenetetrahydrofolate reductase gene (MTHFR 677 C→T) with clinical characteristics, outcome, and therapy-related toxicity in pediatric non-Hodgkin’s lymphoma (NHL) in our multicenter trial NHL-BFM 95. In this trial, high-dose methotrexate (MTX) infusion regimens were randomized (4- vs 24-h infusion) in patients with B-cell lymphoma; MTX was applied as 24-h infusion in all patients with lymphoblastic lymphoma and anaplastic large cell lymphoma. Toxicity data were collected per patient and therapy course according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). The genotypes in 484 pediatric patients were distributed as follows: MTHFR 677 CC, 206 patients (42.6%); MTHFR 677 CT, 214 patients (44.2%); and MTHFR 677 TT, 64 patients (13.2%). Lymphoblastic lymphoma was significantly associated with homozygosity for the MTHFR 677 T allele. No association of MTHFR 677 genotype with clinical characteristics (sex, age, and tumor stage), outcome, or therapy-related toxicity could be detected. Therefore, we conclude that the MTHFR 677 C→T polymorphism does not appear to influence outcome or therapy-associated toxicity in pediatric patients with NHL treated on BFM protocols.


MTHFR Polymorphism Toxicity Pediatric NHL BFM 



We thank E. Odenwald for expert work in cytological diagnosis and U. Meyer for excellent data management. We especially thank all doctors and nurses in participating hospitals for their continuous care for sick children and their excellent cooperation with study center NHL-BFM. Supported by the Deutsche Krebshilfe, Bonn (grant no. M 109/91/Re1) and by the Verein zur Förderung der Behandlung krebskranker Kinder Hannover e.V.


  1. 1.
    Aplenc R, Thompson J, Han P, La M, Zhao H, Lange B, Rebbeck T (2005) Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 15:2482–2487CrossRefGoogle Scholar
  2. 2.
    Bennett JM, Catorsky D, Daniel MT et al (1976) Proposal for the classification of the acute leukemias. French–American–British (FAB) Cooperative Groups. Br J Heamatol 33:451–458CrossRefGoogle Scholar
  3. 3.
    Botto LD, Yang Q (2000) 5,10-methylentetrahydrofolate reductase gene variations and congenital anomalies: a HuGE review. Am J Epidemiol 151:862–877PubMedGoogle Scholar
  4. 4.
    Chiusolo P, Reddiconto G, Casorelli I, Laurenti L, Sora F, Mele L, Leone G, Sica S (2002) Preponderance of methylenetetrahydrofolate reductase C677 homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 13:1915–1918CrossRefPubMedGoogle Scholar
  5. 5.
    Chiusolo P, Reddiconto G, Cimino G, Sica S, Fiorini A, Farina G, Vitale A, Sorà F, Laurenti L, Bartolozzi F, Fazi P, Mandelli F, Leone G (2004) Methylenetetrahydrofolate reductase genotypes do not play a role in acute lymphoblastic leukemia pathogenesis in the Italian population. Haematologica 89:139–144PubMedGoogle Scholar
  6. 6.
    Cox DR (1972) Regression models and life tables. J R Stat Soc 34:187–220Google Scholar
  7. 7.
    Evans WE (2002) Differing effects of methylenetetrahydrofolate reductase single nucleotide polymorphisms on methotrexate efficacy and toxicity in rheumatoid arthritis. Pharmacogenetics 12:181–182CrossRefPubMedGoogle Scholar
  8. 8.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Metthews RG, Boers GHJ, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methyleneterahydrofolate reductase. Nature Genet 10:111–114CrossRefPubMedGoogle Scholar
  9. 9.
    Frosst P, Zhang Z-X, Pai A, Rozen R (1996) The methylenetetrahydrofolate reductase (MTHFR) gene maps to distal mouse chromosome 4. Mamm Genome 7:864–869CrossRefPubMedGoogle Scholar
  10. 10.
    Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Reverberi R, Caruso A, Pasello M, Pellati A, De Mattei M (2004) 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 13:787–794PubMedGoogle Scholar
  11. 11.
    Goyette P, Rozen R (2000) The thermolabile variant 677C-T can further reduce activity when expressed in CIS with severe mutations for human methylenetetrahydrofolate reductase. Hum Mutat 16:132–138CrossRefPubMedGoogle Scholar
  12. 12.
    Greenwood M (1926) A report on the natural duration of cancer. In: Reports on public health and medical subjects. Ministry of Health, Her Majesty’s Statistical Office, London, pp 1–26Google Scholar
  13. 13.
    Harris NL (1997) Principles of the revised European–American Lymphoma Classification (from the International Lymphoma Study Group). Annals Oncol 8:11–16CrossRefGoogle Scholar
  14. 14.
    Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93:7–9PubMedGoogle Scholar
  15. 15.
    Kaplan EL, Meier P (1958) Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  16. 16.
    Kishi K, Griener J, Cheng C, Das S, DCook E, Pei D, Hudson M, Rubnitz J, Sandlund JT, Pui C-H, Relling MV (2003) Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 21:3084–3091CrossRefPubMedGoogle Scholar
  17. 17.
    Koch MC, Stegmann K, Ziegler A, Schroter B, Ermert A (1998) Evaluation of thr MTHFR C677T allele and the MTHFR gene in a German spina bifida population. Eur J Pediatr 157:487–492CrossRefPubMedGoogle Scholar
  18. 18.
    Krajinovic M, Lamothe S, Labuda D, Lemieux-Blanchard E, Théorêt Y, Moghrabi A, Sinnett D (2004) Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood 103:252–257CrossRefPubMedGoogle Scholar
  19. 19.
    Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A (2004) Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics 4:66–72CrossRefGoogle Scholar
  20. 20.
    Krajinovic M, Robaey P, Chiasson S, Lemieux-Blanchard E, Rouillard M, Primeau M, Bournissen FG, Moghrabi A (2005) Polymorphisms of genes controlling homocysteine levels and IQ score following the treatment for childhood ALL. Pharmacogenomics 6:293–302CrossRefPubMedGoogle Scholar
  21. 21.
    Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170PubMedGoogle Scholar
  22. 22.
    Martinelli M, Scapoli L, Pezzetti F, Carinci F, Stabellini G, Bisceglia L, Gombos F, Tognon M (2001) C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers? Am J Hum Genet 98:357–360Google Scholar
  23. 23.
    Matsuo K, Suzuki R, Hamajima M, Ogura M, Kagami Y, Taji H, Kondoh E, Maeda S, Asakura S, Kaba S, Nakamura S, Seto M, Morishima Y, Tajima K (2001) Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant disease. Blood 97:3205–3209CrossRefPubMedGoogle Scholar
  24. 24.
    Mogk RL, Rothenmund H, Evans JA, Carson N, Dawson AJ (2000) The frequency of the C677T substitution in the methylenetetrahydrofolate reductase gene in Manitoba. Clin Genet 58:406–408CrossRefPubMedGoogle Scholar
  25. 25.
    Mornet E, Muller F, Lanvoise-Furet A, Delezoide A-L, Col J-Y, Soimon-Bouy B, Serre J-L (1997) Screening the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects. Hum Genet 100:512–514CrossRefPubMedGoogle Scholar
  26. 26.
    Ogino S, Wilson RB (2003) Genotype and haplotype distributions of MTHFR 677 C>T and 1298 A>C single nucleotide polymorphisms: a meta-analysis. J Hum Genet 48:1–7CrossRefPubMedGoogle Scholar
  27. 27.
    Ortega M, Gomez-de-Segura IA, Vazquez I, Lopez JM, de Guevara CL, De-Miguel E (2001) Effects of growth hormone plus a hyperproteic diet on methotrexate-induced injury in rat intestines. Acta Oncol 40:615–621CrossRefPubMedGoogle Scholar
  28. 28.
    Papapetrou C, Lynch SA, Burn J, Edwards YH (1996) Methylenetetrahydrofolate reductase and neural tube defects. Lancet 348:58–58CrossRefPubMedGoogle Scholar
  29. 29.
    Patte C, Leverger G, Rubie H, Bertrand Y, Coze C, Méchinaud F, Lutz P, Michon J, Baruchel A, Courbon B (1993) High cure rate in B-cell (Burkitt’s) leukemia in the LMB 89 protocol of the SFOP (French Pediatric Oncology Society) (abstract). Proc ASCO 12:317Google Scholar
  30. 30.
    Reinhardt D, Sigusch HH, Vogt SF, Farker K, Muller S, Hoffmann G (1998) Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and the risk of coronary artery disease. Eur J Clin Invest 28:20–23CrossRefPubMedGoogle Scholar
  31. 31.
    Reiter A, Schrappe M, Parwaresch R, Henze G, Müller-Weihrich S, Sauter S, Sykora K-W, Ludwig W-D, Gadner H, Riehm H (1995) Non-Hodgkin’s lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage—a report of the Berlin–Frankfurt–Münster Group. J Clin Oncol 13:359–372PubMedGoogle Scholar
  32. 32.
    Reiter A, Schrappe M, Ludwig W-D, Tiemann M, Parwaresch R, Zimmermann M, Schirg E, Henze G, Schellong G, Gadner H, Riehm H (1999) Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM Group report. Blood 95:416–421Google Scholar
  33. 33.
    Reiter A, Schrappe M, Tiemann M, Ludwig W-D, Yakisan E, Zimmermann M, Mann G, Chott A, Ebell W, Klingebiel T, Graf N, Kremens B, Müller-Weihrich S, Plüss H-J, Zintl F, Henze G, Riehm H (1999) Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin–Frankfurt–Münster Group Trial NHL-BFM 90. Blood 94:3294–3306PubMedGoogle Scholar
  34. 34.
    Seidemann K, Tiemann M, Schrappe M, Yakisan E, Simonitsch I, Janka Schaub G, Dörffel W, Zimmermann M, Mann G, Gadner H, Riehm H, Reiter A (2001) Short-pulse B-non-Hodgkin lymphoma type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin–Frankfurt–Munster Group Trial NHL-BFM 90. Blood 97:3699–3706CrossRefPubMedGoogle Scholar
  35. 35.
    Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96:12810–12815CrossRefPubMedGoogle Scholar
  36. 36.
    Skibola CF, Forrest MS, Coppedé F, Agana L, Hubbard A, Smith MT, Bracci PM, Holly EA (2004) Polymorphisms and haplotypes in folate metabolizing genes and risk of non-Hodgkin lymphoma. Blood 104:2155–2162CrossRefPubMedGoogle Scholar
  37. 37.
    Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T (1997) Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J Med Genet 34:525–526PubMedCrossRefGoogle Scholar
  38. 38.
    Stansfeld AG, Diebold J, Kapanci Y, Noel H, Rilke F, Kelenyi G, Sundstrom C, Lennert J, van Unnik JA, Mioduszewska O (1988) Updated Kiel classification for lymphomas. Lancet 1:292–293CrossRefPubMedGoogle Scholar
  39. 39.
    Stevenson M, Schwartz CE, Du Y-Z, Adams MJ (1997) Differences in methylenetetrahydrofolate reductase genotype frequencies between whites and blacks. Am J Hum Genet 60:229–230PubMedGoogle Scholar
  40. 40.
    Toffoli G, Veronesi A, Boiocchi M, Crivellari D (2000) MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluouracil (CMF). Ann Oncol 11:373–374CrossRefPubMedGoogle Scholar
  41. 41.
    Toffoli G, Rossi D, Gaidano G, Cecchin E, Boiocchi M, Carbone A (2003) Methylenetetrahydrofolate reductase genotype in diffuse large cell lymphomas with and without hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase. Int J Biol Markers 18:218–221PubMedGoogle Scholar
  42. 42.
    Ulrich CM, Storb R, Schubert MM, Potter JD (2001) MTHFR polymorphism, DNA repair capacity, and methotrexate toxicity. Blood 98:2283–2283CrossRefGoogle Scholar
  43. 43.
    Ulrich CM, Robien K, Sparks R (2002) Pharmacogenetics and folate metabolism—a promising direction. Pharmacogenomics 3:299–313CrossRefPubMedGoogle Scholar
  44. 44.
    Urano W, Taniguchi A, Yamanaka H, Tanaka E, Nakajima H, Matsuda Y, Akama H, Kitamura Y, Kamatani N (2002) Polymorphisms in the methylenetetrahydrofolate reductase gene were associated both with the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analysis. Pharmacogenetics 12:183–190CrossRefPubMedGoogle Scholar
  45. 45.
    van der Put NM, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKA, van den Heuvel LP, Mariman ECM, den Heyer M, Rozen R, Blom HJ (1995) Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 346:1070–1071CrossRefPubMedGoogle Scholar
  46. 46.
    van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo TM, van der Putte LB (2001) The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 44:2525–2530CrossRefPubMedGoogle Scholar
  47. 47.
    Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF (2001) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk factor of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci USA 98:4004–4009CrossRefPubMedGoogle Scholar
  48. 48.
    Wössmann W, Seidemann K, Mann G, Zimmermann M, Burkhardt B, Oschlies I, Ludwig WD, Klingebiel T, Graf N, Gruhn B, Jürgens H, Niggli F, Parwaresch R, Gadner H, Riehm H, Schrappe M, Reiter A (2005) The impact of the methotrexate administration schedule and dose in the treatment of children and adolescence with B-cell neoplasms: A report of the BFM Study Group NHL-BFM 95. Blood 105:948–958CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Kathrin Seidemann
    • 1
  • Marion Book
    • 1
  • Martin Zimmermann
    • 1
  • Ulrike Meyer
    • 2
  • Karl Welte
    • 1
  • Martin Stanulla
    • 1
  • Alfred Reiter
    • 2
  1. 1.Department of Pediatric Hematology and OncologyHannover Medical SchoolHannoverGermany
  2. 2.NHL-BFM Study Center, Department of Pediatric Hematology and OncologyUniversity Children’s Hospital, Justus Liebig University GiessenGiessenGermany

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