Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma

Abstract

Inter-individual differences in toxic symptoms and pharmacokinetics of highdose 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 AUC 0-48 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.

Risk factors associated with delayed methotrexate clearance and increased toxicity in pediatric patients with osteosarcoma

“…Compared with Hispanic patients, black patients were also significantly more likely to experience these toxicities, but less likely than white patients. This strong association between race/ethnicity and adverse treatment outcomes suggests an intrinsic genetic disposition to MTX therapy, which could be mediated by single‐nucleotide polymorphisms, including germline variants in biliary and renal membrane transporters previously reported as mediators of MTX's pharmacokinetic variability …”

“…This strong association between race/ethnicity and adverse treatment outcomes suggests an intrinsic genetic disposition to MTX therapy, which could be mediated by single-nucleotide polymorphisms, including germline variants in biliary and renal membrane transporters previously reported as mediators of MTX's pharmacokinetic variability. 16,17 Overall, we have described the pharmacologic risk profile of HD-MTX in a cohort of pediatric patients with OS. Risk factors described in our study should be considered at the time of design of new protocols for outpatient administration of HD-MTX in pediatric OS.…”

A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High‐Dose Methotrexate: Data From the OS2006/Sarcoma‐09 Trial

“…It is located in a noncoding region, and no linkage disequilibrium with a nonsynonymous SNP located in a coding region has been shown. Interestingly, in a recent study Hegyi et al 23 also reported a correlation between polymorphisms of the ABCG2 gene and MTX elimination half-life. Furthermore, it was shown that the rs13120400 was correlated to MTX efficacy in a cohort of 340 patients with psoriasis.…”

Long Noncoding RNAs in Osteosarcoma: Mechanisms and Potential Clinical Implications

“…Lung cancer associated transcript 1 (LUCAT1) lncRNA has been found to be overexpressed in osteosarcoma tissue samples and in MG63 and HOX osteosarcoma cell lines resistant to methotrexate, a drug that is used widely in osteosarcoma patients [233][234][235]. MG63 and HOX, resistant to methotrexate, also overexpress the ATP-binding cassette subfamily B member 1 (ABCB1), a drug resistance-related protein.…”