title: Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.
abstract: Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Marta
authors: M
authors: Hegyi
authors: Department of Measurement and Information Systems, University of Technology and Economics, H-1111 Budapest, Műegyetem rkp. 3, Hungary.|Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hőgyes Endre u. 7, Hungary.
authors: Adam
authors: A
authors: Arany
authors: Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Nagyvárad tér 4, Hungary.
authors: Agnes F
authors: AF
authors: Semsei
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Katalin
authors: K
authors: Csordas
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Oliver
authors: O
authors: Eipel
authors: Department of Measurement and Information Systems, University of Technology and Economics, H-1111 Budapest, Műegyetem rkp. 3, Hungary.|Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Nagyvárad tér 4, Hungary.
authors: Andras
authors: A
authors: Gezsi
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.|Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Nagyvárad tér 4, Hungary.
authors: Nora
authors: N
authors: Kutszegi
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Monika
authors: M
authors: Csoka
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Judit
authors: J
authors: Muller
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Daniel J
authors: DJ
authors: Erdelyi
authors: Department of Measurement and Information Systems, University of Technology and Economics, H-1111 Budapest, Műegyetem rkp. 3, Hungary.
authors: Peter
authors: P
authors: Antal
authors: Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Nagyvárad tér 4, Hungary.
authors: Csaba
authors: C
authors: Szalai
authors: Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary.
authors: Gabor T
authors: GT
authors: Kovacs
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001499:Bayes Theorem; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016009:Chi-Square Distribution; D002648:Child; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D015999:Multivariate Analysis; D016017:Odds Ratio; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D016896:Treatment Outcome; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011623:gamma-Glutamyl Hydrolase; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C000625852:NR1I2 protein, human; C114462:multidrug resistance-associated protein 3
keywords: Bayesian network-based Bayesian multilevel analysis of relevance (BN-BMLA); SNP; methotrexate; osteosarcoma; toxicity