Original Article

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

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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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Author information

Author notes

    • C Zhu
    •  & Y W Liu

    These authors contributed equally to this work and should be considered co-first authors.

Affiliations

  1. Department of Pharmacy, Beijing Children’s Hospital, Capital Medical University, Beijing, China

    • C Zhu
    • , Y W Liu
    • , S Z Wang
    • , X L Nie
    • , X T Yu
    • , L B Zhao
    •  & X L Wang
  2. Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, China

    • C Zhu
    •  & X L Li
  3. Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China

    • X T Yu

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to X L Wang.

Appendices

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

Appendix 2

Appendix 2 Search strategy for PubMed

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

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

    1. Methotrexate/ or methotrexate.mp.

    2. mexate or amethopterin.mp.

    3. MTX.mp

    4. or/1-3

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

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

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

    3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/

    4. or/1-3

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

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

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

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

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

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

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

    12. or/5-11

    13. 4 or 12

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

    1. methylenetetrahydrofolate reductase.mp. or Methylenetetrahydrofolate Reductase/

    2. (MTHFR or NADPH2).mp.

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

    4. EC 1.1.1.171.mp.

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

    6. 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]