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Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute
Nina Erčulj1, Barbara Faganel Kotnik, Maruša Debeljak
1Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia.
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.
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