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Polymorphisms of genes related to metotrexate response and toxicity in high-grade osteosarcoma

To implement the information reported in our review entitled ‘Pharmacogenomics of genes involved in antifolate drug response and toxicity in osteosarcoma’ [1], we would like to discuss here the recent data by Hegyi and coworkers [2]. This study correlated pharmacogenetic data with pharmacokinetic parameters and toxicity related to high-dose metotrexate (MTX) treatment in a homogeneously treated series of 59 pediatric patients with high-grade osteosarcoma (HGOS). Twenty-nine single-nucleotide polymorphisms (SNPs) of seven metotrexate (MTX) transporter genes (ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, and SLC19A1) and gamma-glutamyl hydrolase (GGH) were genotyped. Data were elaborated by univariate association and Bayesian network-based univariate and multilevel analyses of relevance. Associations between genotype status andMTX half-life, area under the concentration-time curve (AUC0-48), the peak MTX and 48-hour MTX levels, hepatotoxicity as well as myelotoxicity were determined. Among the genes that are directly involved in the metabolism or transport of MTX, higher risk for myelotoxicity was associated with the variant allele of ABCC2 rs2273697, which is concordant with the observation recently published by us in a series of 57 HGOS patients [3]. Lower risk for myelotoxicity and lower AUC0-48 were associated with the variant alleles of ABCC2 rs3740066. The variant allele of ABCB1 rs9282564 was associated with higher peak MTX levels and AUC0-48 of concentration time curves. Although this polymorphism has been studied in relation to several drugs and did not influence protein expression or transport function [4], no direct influence on the pharmacokinetics of MTX has been reported in vitro so far. Variant alleles of ABCG2 rs2231142 were associated with increased MTX half-life, whereas ABCC3 rs4793665 was related to a decreased AUC0-48. Interestingly, the application of Bayesian network-based Bayesian univariate and multivariate analysis of relevance detected a relevant effect of ABCB1 rs9282564, ABCC3 rs4793665, and GGH rs3758149 on the cluster of target variables, pharmacokinetic and toxicity related to MTX. This study further confirms that several SNPs of genes related to folate metabolism and transport may have impact on MTX kinetics and toxicity in patients with HGOS.