title: Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia.
abstract: Methotrexate (MTX) is commonly used agent in therapy of malignancies, including acute lymphoblastic leukemia (ALL). Based on the literature data it is known that MTX elimination and toxicity can be affected by polymorphisms in genes encoding enzymes involved in MTX metabolism. The aim of our study was to investigate the influence of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene on MTX-induced toxicity during treatment of children with ALL. We also tried to answer the question whether simultaneous occurrence of these two polymorphisms has a clinical significance. MTHFR polymorphisms were assessed in 47 pediatric ALL patients, treated according to intensive chemotherapy for childhood ALL, ALL IC BFM 2009. Prolonged MTX elimination and higher incidence of toxicity were observed for patients with 677T-1298A haplotype. On the other hand, occurrence of 677C-1298A haplotype had protective effect on MTX clearance and toxicity, that was not observed in carriers of 677C-1298C haplotype. In patients with coexistence of studied variants 677CT/1298AC heterozygotes as well as in 677TT/1298AA homozygotes more frequently toxicity incidents were noted. The obtained results suggest that occurrence of 677T allele and coexistence of 677T and 1298C alleles may be associated with lower MTX clearance and elevated risk of adverse effects during MTX-treatment of pediatric ALL patients.
authors.affiliation: Institute of Human Genetics Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Kałużna
authors.affiliation: Institute of Human Genetics Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland; Poznan University of Medical Sciences, Laboratory for Basic Research and Translational Medicine, Clinic of Internal and Vascular Surgery, Długa 1/2, 61-848 Poznań, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Strauss
authors.affiliation: Poznań University of Medical Sciences, Department of Oncology, Hematology and Bone Marrow Transplantation, Szpitalna 27/33, 60-572 Poznań, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Zając-Spychała
authors.affiliation: Poznań University of Medical Sciences, Family Medicine Department, Przybyszewskiego 49, 60-355 Poznan, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Gowin
authors.affiliation: Institute of Human Genetics Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland.
authors.forename: Bogna
authors.initials: B
authors.lastname: Świątek-Kościelna
authors.affiliation: Institute of Human Genetics Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Institute of Human Genetics Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Fichna
authors.affiliation: Poznań University of Medical Sciences, Department of Paediatric Surgery Traumatology and Urology, Szpitalna 27/33, 60-572 Poznan, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Mańkowski
authors.affiliation: Institute of Human Genetics Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland; Poznań University of Medical Sciences, Department of Oncology, Hematology and Bone Marrow Transplantation, Szpitalna 27/33, 60-572 Poznań, Poland; Department of Medical Diagnostics, Dobra 38a, 60-595 Poznan, Poland. Electronic address: janusz@man.poznan.pl.
authors.forename: Danuta
authors.initials: D
authors.lastname: Januszkiewicz-Lewandowska
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate
keywords: Acute lymphoblastic leukemia; Folate metabolism; MTHFR polymorphism