Author/Editor		Erčulj, Nina; Faganel-Kotnik, Barbara; Debeljak, Maruša; Jazbec, Janez; Dolžan, Vita
Title		Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia
Type		članek
Source		Leuk Lymphoma
Vol. and No.		Letnik 53, št. 6
Publication year		2012
Volume		str. 1096-104
Language		eng
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. MTHFD1 1958A allele significantly reduced odds of hepatotoxicity (adjusted P=0.009), while TYMS 3R allele significantly reduced 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 folate pathway in HD-MTX-related toxicity in childhood ALL.
Descriptors		LEUKEMIA, LYMPHOCYTIC, ACUTE METHOTREXATE POLYMORPHISM (GENETICS) GENOTYPE METHYLENETETRAHYDROFOLATE DEHYDROGENASE CHILD THYMIDYLATE SYNTHETASE ALLELES TREATMENT OUTCOME