title: Influence of methylenetetrahydrofolate reductase gene polymorphisms on the outcome of pediatric patients with non-Hodgkin lymphoma treated with high-dose methotrexate.
abstract: High-dose methotrexate (MTX) is a key component of most treatment protocols for childhood and adolescent non-Hodgkin lymphoma (NHL). Recent studies have suggested that the toxicity of antifolate drugs, such as MTX, is affected by inherited single nucleotide polymorphisms (SNPs) in folate metabolizing genes. The aim of our study was to investigate the potential influence of the C677T and A1298C genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene on the clinical toxicity and efficacy of MTX in pediatric patients with NHL (n = 95) treated with therapeutic protocols Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 and EURO LB-02. We demonstrated that patients with the 677T genotype had an approximately six-fold greater risk of developing hematological toxicity compared with wild-type carriers, especially in the 1 g/m(2) treatment group (p = 0.01). Moreover, we identified a correlation between the risk of relapse and the T genotype: T carriers had reduced disease-free survival compared with wild-type patients (67% vs. 100%). Our data suggest a pharmacogenetic influence on the adverse effects of high-dose MTX in the 1 g/m(2) treatment group.
authors.affiliation: Department of Woman, Children and General and Specialized Surgery, Second University of Naples , Italy.
authors.forename: Velia
authors.initials: V
authors.lastname: D'Angelo
authors.forename: Maria
authors.initials: M
authors.lastname: Ramaglia
authors.forename: Adriana
authors.initials: A
authors.lastname: Iannotta
authors.forename: Matteo
authors.initials: M
authors.lastname: Francese
authors.forename: Elvira
authors.initials: E
authors.lastname: Pota
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Affinita
authors.forename: Giulia
authors.initials: G
authors.lastname: Pecoraro
authors.forename: Cristiana
authors.initials: C
authors.lastname: Indolfi
authors.forename: Martina
authors.initials: M
authors.lastname: Di Martino
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Pinto
authors.forename: Salvatore
authors.initials: S
authors.lastname: Buffardi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Poggi
authors.forename: Paolo
authors.initials: P
authors.lastname: Indolfi
authors.forename: Fiorina
authors.initials: F
authors.lastname: Casale
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D043922:Toxicogenetics; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate