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

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.