title: Pharmacogenetic studies in children with acute lymphoblastic leukemia in Argentina.
abstract: The aim of this study was to evaluate the influence of the most common genetic variants in methylenetetrahydrofolate reductase (MTHFR), thiopurine methyltransferase (TPMT) and glutathione-S-transferases (GSTs) on the outcome of acute lymphoblastic leukemia (ALL) treatment in Argentinean children. Two hundred and eighty-six patients with ALL treated with two Berlin-Frankfurt-Münster (BFM)-based protocols were analyzed. Ten genetic variants were studied. Toxicity was evaluated during the consolidation phase. Children who received 2 g/m(2)/day of methotrexate and carried at least one 677T allele in MTHFR showed an increased risk of developing severe leukopenia (p = 0.004) and neutropenia (p = 0.003). Intermediate-risk (IR) patients with a heterozygous TPMT genotype had a higher probability of event-free survival than those with a wild-type genotype. Genotyping of MTHFR polymorphisms might be useful to optimize consolidation therapy, reducing the associated severe hematologic toxicity. Further studies are necessary to establish the usefulness of MTHFR and TPMT variants as additional markers to predict outcome in the IR group.
authors.affiliation: Laboratory of Molecular Biology, Genetics Department, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan" , Ciudad de Buenos Aires , Argentina.
authors.forename: Hilda Verónica
authors.initials: HV
authors.lastname: Aráoz
authors.forename: Karina
authors.initials: K
authors.lastname: D'Aloi
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Foncuberta
authors.forename: Christian Germán
authors.initials: CG
authors.lastname: Sanchez La Rosa
authors.forename: Cristina Noemí
authors.initials: CN
authors.lastname: Alonso
authors.forename: Lilien
authors.initials: L
authors.lastname: Chertkoff
authors.forename: Marisa
authors.initials: M
authors.lastname: Felice
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001118:Argentina / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases; C022745:thiopurine methyltransferase
keywords: ALL; GSTs; MTHFR; TPMT; pediatrics; pharmacogenetics