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Pharmacogenomics J. 2014 Apr;14(2):115-9. doi: 10.1038/tpj.2013.19. Epub 2013 May 7.

The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer.

Author information

  • 1Department of Pediatric Hematology and Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 2Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 3Division of Oncology, The Children's Hospital of Philadelphia, PA, USA.
  • 4Laboratory of Pediatrics, University Clinic of Navarra, Pamplona, Spain.
  • 5Hematology Department, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 6Department of Biomedical Sciences and Advanced Therapies, Center Study Haemostasis and Thrombosis, University of Ferrara, Ferrara, Italy.
  • 7Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
  • 8Department of Pediatrics, Université de Montréal, Québec, Canada.
  • 91] Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands [2] Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre, Nijmegen, The Netherlands.


Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.

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