title: Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia.
abstract: The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial who received 1996 courses of MTX at 5 g/m(2) were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26% (P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R(2) = 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R(2) = 0.018; P = .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P = .015) with event-free survival in the ALL-BFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL.
authors: Department for Pediatric Oncology and Immunology, Late Effects Surveillance System Center, University Hospital for Children and Adolescents, Erlangen, Germany.
authors: Susanne
authors: S
authors: Radtke
authors: Oliver
authors: O
authors: Zolk
authors: Bertold
authors: B
authors: Renner
authors: Marios
authors: M
authors: Paulides
authors: Martin
authors: M
authors: Zimmermann
authors: Anja
authors: A
authors: Möricke
authors: Martin
authors: M
authors: Stanulla
authors: Martin
authors: M
authors: Schrappe
authors: Thorsten
authors: T
authors: Langer
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007223:Infant; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000493:pharmacokinetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009367:Neoplasm Staging; D018365:Neoplasm, Residual; D027361:Organic Anion Transporters / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D013280:Stomatitis / Q000139:chemically induced / Q000235:genetics; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D027381:Liver-Specific Organic Anion Transporter 1; D008727:Methotrexate; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D058978:Reduced Folate Carrier Protein; D013940:Thymidylate Synthase; C548699:SLC19A1 protein, human; C503999:SLCO1B1 protein, human; C573423:MTHFR protein, human