title: Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia.
abstract: The prediction of high-dose methotrexate (HD-MTX) toxicity is a key issue in the individualization of treatment in childhood acute lymphoblastic leukemia (ALL). Our aim was to evaluate the influence of MTX pathway polymorphisms on HD-MTX treatment outcome in children with ALL. In total, 167 children with ALL were genotyped for methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G > A, methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C and thymidylate synthase (TYMS) 2R > 3R polymorphisms. The MTHFD1 1958A allele significantly reduced the odds of hepatotoxicity (adjusted p = 0.009), while the TYMS 3R allele significantly reduced the odds of leukocytopenia and thrombocytopenia (adjusted p = 0.005 and adjusted p = 0.002, respectively). MTHFR polymorphisms did not influence HD-MTX-related toxicity, but a significant effect of MTHFR 677C > T-TYMS 2R > 3R and MTHFD1 1958G > A-MTHFR 677C > T interactions on HD-MTX-related toxicity was observed. None of the investigated polymorphisms influenced survival. Our study suggests an important role of polymorphisms and gene-gene interactions within the folate pathway in HD-MTX-related toxicity in childhood ALL.
authors.affiliation: Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Nina
authors.initials: N
authors.lastname: Erčulj
authors.forename: Barbara Faganel
authors.initials: BF
authors.lastname: Kotnik
authors.forename: Maruša
authors.initials: M
authors.lastname: Debeljak
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
authors.forename: Vita
authors.initials: V
authors.lastname: Dolžan
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality*; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D013940:Thymidylate Synthase; D008727:Methotrexate