4106 ORAL Polymorphisms in Methotrexate Transport Pathway – a New Tool for Toxicity Prevention in Pediatric Acute Lymphoblastic Leukemia

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for 30% of all pediatric malignancies.Remarkable progress has been made in the treatment of acute lymphoblastic leukemia (ALL): four decades ago, the cure rate was less than 10%, today it is nearly 80%.An important component of ALL therapy is methotrexate (MTX).Treatment with MTX often causes toxicity, dose reduction or cessation of treatment being necessary.Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes.In the last years, several studies have investigated the relationship between genetic variation and MTX-related toxicity.Recently, in our group, considering MTX clearance as an objectively quantifiable toxicity criterion, we have confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity, previously proposed by Trevino and collaborators.As SLCO1B1 is a hepatic transporter involved in MTX elimination, polymorphisms in transporter genes from the same pathway could also have a role in MTX toxicity.As a result, in the present study, we have evaluated polymorphisms in 12 genes of MTX transport as toxicity predictors in pediatric B-ALL, all of them homogeneously treated according to the standardized LAL/SHOP protocol.Material and Methods: DNA was extracted from blood samples of 150 paediatric ALL patients treated with the LAL/SHOP protocol by standard phenol-chloroform method.We genotyped 384 SNPs in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) with Illumina Golden Gate platform and we analyzed their correlation with MTX toxicity.Results: We confirmed that polymorphisms in transporter genes are associated with MTX clearance.Conclusions: Our results suggest that polymorphisms in genes involved in MTX transport could be new toxicity markers in pediatric ALL.This project was supported by RETICS (RD/06/0020/0048) and Basque Government (GIC10/71, SAI10/03 and 2006111015).Support by SGIker (UPV/EHU) is gratefully acknowledged.