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Associations between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in childhood malignancies: a meta-analysis

Abstract

As a common chemotherapy drug, methotrexate (MTX) has achieved remarkable clinical success. However, high inter-individual variability and unpredictable toxicity continue to challenge its use in clinical practices. Some studies suggest this variation is associated with a methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, but results remain unclear. In this meta-analysis, we include 14 studies that focus on MTHFR C677T and A1298C polymorphisms in pediatric patients with malignancy. We found significant associations of the MTHFR C677T polymorphism with hepatotoxicity (grade 2; CC vs CT/TT: risk ratio (RR): 0.82, 95% confidence interval (CI): 0.67–0.99; P=0.04), hematological toxicity (grade 3–4; CC vs CT/TT: RR: 0.65, 95% CI: 0.44–0.97; P=0.03) in a dominant genetic model and mucositis (grade 3) in all models (CC vs CT/TT: RR: 0.18, 95% CI: 0.04–0.87; P=0.03; CC/CT vs TT: RR: 0.10, 95% CI: 0.03–0.32; P0.0001; CC vs TT: RR: 0.10, 95% CI: 0.02–0.50; P=0.005). No significant association was found with the MTHFR A1298C polymorphism. For children with malignancy, genotyping of the MTHFR C677T polymorphism is expected to be a useful tool in reducing toxicity and improving outcome in personalized MTX therapy.

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References

  1. Johnston WT, Lightfoot TJ, Simpson J, Roman E . Childhood cancer survival: a report from the United Kingdom Childhood Cancer Study. Cancer Epidemiol 2010; 34: 659–666.

    Article  PubMed  Google Scholar 

  2. Pui CH . Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia. Front Med 2015; 9: 1–9.

    Article  PubMed  Google Scholar 

  3. Zhao M, Liang L, Ji L, Chen D, Zhang Y, Zhu Y et al. MTHFR gene polymorphisms and methotrexate toxicity in adult patients with hematological malignancies: a meta-analysis. Pharmacogenomics 2016; 17: 1005–1017.

    Article  CAS  PubMed  Google Scholar 

  4. Liu SG, Li ZG, Cui L, Gao C, Li WJ, Zhao XX . Effects of methylenetetrahydrofolate reductase gene polymorphisms on toxicities during consolidation therapy in pediatric acute lymphoblastic leukemia in a Chinese population. Leuk Lymphoma 2011; 52: 1030–1040.

    Article  CAS  PubMed  Google Scholar 

  5. Park JA, Shin HY . Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma. Blood Res 2016; 51: 50–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. de Jonge R, Tissing WJ, Hooijberg JH, Jansen G, Kaspers GJ, Lindemans J et al. Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 2009; 113: 2284–2289.

    Article  CAS  PubMed  Google Scholar 

  7. Gorlick R, Goker E, Trippett T, Waltham M, Banerjee D, Bertino JR . Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med 1996; 335: 1041–1048.

    Article  CAS  PubMed  Google Scholar 

  8. Stamp LK, Roberts RL . Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases. Pharmacogenomics 2011; 12: 1449–1463.

    Article  CAS  PubMed  Google Scholar 

  9. Bellampalli R, Phani NM, Bhat KG, Prasad K, Bhaskaranand N, Guruprasad KP et al. Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis. Leuk Lymphoma 2015; 56: 1450–1459.

    Article  CAS  PubMed  Google Scholar 

  10. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.

    Article  CAS  PubMed  Google Scholar 

  11. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang L, Tissing WJE, de Jonge R, van Zelst BD, Pieters R . Polymorphisms in folate-related genes: Association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Leukemia 2008; 22: 1798–1800.

    Article  CAS  PubMed  Google Scholar 

  13. Yang L, Hu X, Xu L . Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol 2012; 33: 1445–1454.

    Article  CAS  PubMed  Google Scholar 

  14. Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A . A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 2013; 13: 498–506.

    Article  CAS  PubMed  Google Scholar 

  15. Hagleitner MM, Coenen MJ, Aplenc R, Patino-Garcia A, Chiusolo P, Gemmati D et al. The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer. Pharmacogenomics J 2014; 14: 115–119.

    Article  CAS  PubMed  Google Scholar 

  16. Campbell JM, Bateman E, Stephenson MD, Bowen JM, Keefe DM, Peters MD . Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chem Pharmacol 2016; 78: 27–39.

    Article  CAS  Google Scholar 

  17. D'Angelo V, Ramaglia M, Iannotta A, Francese M, Pota E, Affinita MC et al. Influence of methylenetetrahydrofolate reductase gene polymorphisms on the outcome of pediatric patients with non-Hodgkin lymphoma treated with high-dose methotrexate. Leuk Lymphoma 2013; 54: 2639–2644.

    Article  CAS  PubMed  Google Scholar 

  18. Zgheib NK, Akra-Ismail M, Aridi C, Mahfouz R, Abboud MR, Solh H et al. Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics 2014; 24: 387–396.

    CAS  PubMed  Google Scholar 

  19. Araoz HV, D'Aloi K, Foncuberta ME, Sanchez La Rosa CG, Alonso CN, Chertkoff L et al. Pharmacogenetic studies in children with acute lymphoblastic leukemia in Argentina. Leuk Lymphoma 2015; 56: 1370–1378.

    Article  CAS  PubMed  Google Scholar 

  20. Moulik NR, Kumar A, Agrawal S, Awasthi S, Mahdi AA, Kumar A . Role of folate status and methylenetetrahydrofolate reductase genotype on the toxicity and outcome of induction chemotherapy in children with acute lymphoblastic leukemia. Leuk Lymphoma 2015; 56: 1379–1384.

    Article  Google Scholar 

  21. Moher D, Liberati A, Tetzlaff J, Altman DG . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010; 8: 336–341.

    Article  Google Scholar 

  22. DerSimonian R, Laird N . Meta-analysis in clinical trials revisited. Contemp Clin Trials 2015; 45 (Pt A): 139–145.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tantawy AA, El-Bostany EA, Adly AA, Abou El Asrar M, El-Ghouroury EA, Abdulghaffar EE . Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2010; 21: 28–34.

    Article  CAS  PubMed  Google Scholar 

  24. D'Angelo V, Ramaglia M, Iannotta A, Crisci S, Indolfi P, Francese M et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 2011; 68: 1339–1346.

    Article  CAS  PubMed  Google Scholar 

  25. Karathanasis NV, Stiakaki E, Goulielmos GN, Kalmanti M . The role of the methylenetetrahydrofolate reductase 677 and 1298 polymorphisms in Cretan children with acute lymphoblastic leukemia. Genet Test Mol Biomarkers 2011; 15: 5–10.

    Article  CAS  PubMed  Google Scholar 

  26. Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D et al. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 2003; 21: 3084–3091.

    Article  CAS  PubMed  Google Scholar 

  27. Imanishi H, Okamura N, Yagi M, Noro Y, Moriya Y, Nakamura T et al. Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. J Hum Genet 2007; 52: 166–171.

    Article  CAS  PubMed  Google Scholar 

  28. Shimasaki N, Mori T, Torii C, Sato R, Shimada H, Tanigawara Y et al. Influence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia or lymphoma. J Pediatr Hematol Oncol 2008; 30: 347–352.

    Article  CAS  PubMed  Google Scholar 

  29. Horinouchi M, Yagi M, Imanishi H, Mori T, Yanai T, Hayakawa A et al. Association of genetic polymorphisms with hepatotoxicity in patients with childhood acute lymphoblastic leukemia or lymphoma. Pediatr Hematol Oncol 2010; 27: 344–354.

    Article  CAS  PubMed  Google Scholar 

  30. Sepe DM, McWilliams T, Chen J, Kershenbaum A, Zhao H, La M et al. Germline genetic variation and treatment response on CCG-1891. Pediatr Blood Cancer 2012; 58: 695–700.

    Article  PubMed  Google Scholar 

  31. Fisher MC, Cronstein BN . Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 2009; 36: 539–545.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lee YH, Song GG . Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxicity of methotrexate in rheumatoid arthritis: a meta-analysis. Clin Drug Invest 2010; 30: 101–108.

    Article  CAS  Google Scholar 

  33. Spyridopoulou KP, Dimou NL, Hamodrakas SJ, Bagos PG . Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis. Pharmacogenet Genomics 2012; 22: 117–133.

    Article  CAS  PubMed  Google Scholar 

  34. Owen SA, Lunt M, Bowes J, Hider SL, Bruce IN, Thomson W et al. MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms. Pharmacogenomics J 2013; 13: 137–147.

    Article  CAS  PubMed  Google Scholar 

  35. Song GG, Bae SC, Lee YH . Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol 2014; 33: 1715–1724.

    Article  PubMed  Google Scholar 

  36. Salazar J, Altes A, del Rio E, Estella J, Rives S, Tasso M et al. Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia. Pharmacogenomics J 2012; 12: 379–385.

    Article  CAS  PubMed  Google Scholar 

  37. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A . Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 2004; 4: 66–72.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to X L Wang.

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The authors declare no conflict of interest.

Appendix 1

Appendix 1 Search strategy for Cochrane Library

The following text words were used:

methotrexate OR MTX OR mexate OR amethopterin

The search was performed in title, abstract or keywords

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Appendices

Appendix 2

Appendix 2 Search strategy for PubMed

  1. 1

    For methotrexate the following MeSH headings and text words were used:methotrexate OR MTX OR mexate OR amethopterin

  2. 2

    For children, the following MeSH headings and text words were used:infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR schools, nursery OR infant, newborn

  3. 3

    For MTHFR, the following MeSH headings and text words were used:MTHFR OR methylenetetrahydrofolate reductase OR 5,10-methylenetetrahydrofolate reductase OR methylenetetrahydrofolate, reductase OR FADH OR FADH2 OR EC 1.1.1.171. OR NADPH OR NAD* OR NAD*H methylene-THF reductase OR NADPH2 OR methylene tetrahydrofolate reductase OR tetrahydrofolate reductase, methyleneFinal search: 1 AND 2 AND 3[*=zero or more characters]

Appendix 3

Appendix 3 Search strategy for Embase

  1. 1

    For methotrexate, the following Emtree terms and text words were used:

    1. a

      Methotrexate/ or methotrexate.mp.

    2. b

      mexate or amethopterin.mp.

    3. c

      MTX.mp

    4. d

      or/1-3

  2. 2

    For children, the following Emtree terms and text words were used:?

    1. a

      infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/

    2. b

      adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/

    3. c

      primary school/ or high school/ or kindergarten/ or nursery school/ or school/

    4. d

      or/1-3

    5. e

      (infant$ or (newborn$ or new born$) or (baby or baby$ or babies) or neonate$).mp.

    6. f

      (child$ or (school child$ or schoolchild$) or (school age$ or schoolage$) or (pre school$ or preschool$)).mp.

    7. g

      (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.

    8. h

      (minors$ or (under ag$ or underage$) or juvenil$ or youth$).mp.

    9. i

      (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.

    10. j

      (pediatric$ or paediatric$ or peadiatric$).mp.

    11. k

      (school or schools or (high school$ or highschool$) or primary school$ or nursery school$ or elementary school or secondary school$ or kindergar$).mp.

    12. l

      or/5-11

    13. m

      4 or 12

  3. 3

    For MTHFR, the following Emtree terms and text words were used:

    1. a

      methylenetetrahydrofolate reductase.mp. or Methylenetetrahydrofolate Reductase/

    2. b

      (MTHFR or NADPH2).mp.

    3. c

      (methylene-THF reductase or methylene tetrahydrofolate reductase).mp.

    4. d

      EC 1.1.1.171.mp.

    5. e

      (NADPH or NAD$ or FADH2 or FADH$).mp.

    6. f

      or/1-5

Final search: 1 and 2 and 3 (Methotrexate AND Children AND MTHFR) [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; /=Emtree term; $=zero or more characters]

Appendix 4

Search strategy for Web of Science

The following text words were used:

(Methotrexate OR MTX) AND (child* OR pediatric* OR p*diatric*) AND (MTHFR OR methylenetetrahydrofolate reductase)

The search was performed in subject headings

[*=zero or more characters]

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Zhu, C., Liu, Y., Wang, S. et al. Associations between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in childhood malignancies: a meta-analysis. Pharmacogenomics J 18, 450–459 (2018). https://doi.org/10.1038/tpj.2017.34

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