Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma
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Marta Hegyi1, Adam Arany2,3, Agnes F. Semsei4, Katalin Csordas1, Oliver Eipel1, Andras Gezsi2,4, Nora Kutszegi1,4, Monika Csoka1, Judit Muller1, Daniel J. Erdelyi1, Peter Antal2, Csaba Szalai4, Gabor T. Kovacs1
1Second Department of Pediatrics, Semmelweis University, H-1094 Budapest, Tűzoltó utca 7-9, Hungary
2Department of Measurement and Information Systems, University of Technology and Economics, H-1111 Budapest, Műegyetem rkp. 3, Hungary
3Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hőgyes Endre u. 7, Hungary
4Department of Genetics, Cell and Immunobiology, Semmelweis University, H-1089 Budapest, Nagyvárad tér 4, Hungary
Gabor T. Kovacs, email: [email protected]
Keywords: osteosarcoma, methotrexate, toxicity, SNP, Bayesian network-based Bayesian multilevel analysis of relevance (BN-BMLA)
Received: February 18, 2016 Accepted: August 09, 2016 Published: August 23, 2016
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.
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