Objectives Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Treviño and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL. Methods We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol. Results A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated. Conclusion Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.

Aim: Vincristine is an important component of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. Recently, a genome-wide association study connected a SNP in CEP72, involved in vincristine pharmacodynamics, with neurotoxicity during later phases of therapy, which was not replicated during induction phase. These results, together with previous studies indicating that polymorphisms in pharmacokinetic genes are associated with drug toxicity, suggest that changes in the activity or levels of vincristine transporters or metabolizers could work as predictors of vincristine-related neurotoxicity in early phases of treatment in pediatric ALL. Patients & methods: We analyzed 150 SNPs in eight key genes involved in vincristine pharmacokinetics and in 13 miRNAs that regulate them. We studied their correlation with neurotoxicity during induction phase in 152 ALL ...