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; P⩽0.0001; 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.
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 Search strategy for PubMed
For methotrexate the following MeSH headings and text words were used:methotrexate OR MTX OR mexate OR amethopterin
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
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 184.108.40.206. 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 Search strategy for Embase
For methotrexate, the following Emtree terms and text words were used:
Methotrexate/ or methotrexate.mp.
mexate or amethopterin.mp.
For children, the following Emtree terms and text words were used:?
infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/
primary school/ or high school/ or kindergarten/ or nursery school/ or school/
(infant$ or (newborn$ or new born$) or (baby or baby$ or babies) or neonate$).mp.
(child$ or (school child$ or schoolchild$) or (school age$ or schoolage$) or (pre school$ or preschool$)).mp.
(kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
(minors$ or (under ag$ or underage$) or juvenil$ or youth$).mp.
(puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
(pediatric$ or paediatric$ or peadiatric$).mp.
(school or schools or (high school$ or highschool$) or primary school$ or nursery school$ or elementary school or secondary school$ or kindergar$).mp.
4 or 12
For MTHFR, the following Emtree terms and text words were used:
methylenetetrahydrofolate reductase.mp. or Methylenetetrahydrofolate Reductase/
(MTHFR or NADPH2).mp.
(methylene-THF reductase or methylene tetrahydrofolate reductase).mp.
(NADPH or NAD$ or FADH2 or FADH$).mp.
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]
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]