title: Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.
abstract: OBJECTIVE
  Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine.
  
  
  METHODS
  Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool.
  
  
  RESULTS
  Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia.
  
  
  CONCLUSIONS
  This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.
authors.affiliation: The Joanna Briggs Institute, Faculty of Health Science, University of Adelaide, 115 Grenfell Street, Adelaide, SA, Australia. jared.campbell@adelaide.edu.au.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Campbell
authors.affiliation: School of Medicine, Faculty of Health Science, University of Adelaide, Frome Road, Adelaide, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Bateman
authors.affiliation: The Joanna Briggs Institute, Faculty of Health Science, University of Adelaide, 115 Grenfell Street, Adelaide, SA, Australia.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Stephenson
authors.affiliation: School of Medicine, Faculty of Health Science, University of Adelaide, Frome Road, Adelaide, Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
authors.affiliation: School of Medicine, Faculty of Health Science, University of Adelaide, Frome Road, Adelaide, Australia.
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: Keefe
authors.affiliation: The Joanna Briggs Institute, Faculty of Health Science, University of Adelaide, 115 Grenfell Street, Adelaide, SA, Australia.
authors.forename: Micah D J
authors.initials: MD
authors.lastname: Peters
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D005838:Genotype; D060005:Genotyping Techniques / Q000379:methods; D006801:Humans; D015201:Meta-Analysis as Topic; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D010597:Pharmacogenetics; D057285:Precision Medicine; D000078202:Systematic Reviews as Topic
chemical_list: D000964:Antimetabolites, Antineoplastic; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate
keywords: Cancer; Chemotherapy; Methotrexate; Personalized medicine; Pharmacogenetics; Toxicity