title: Polymorphisms in the methotrexate transport pathway:  a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Elixabet
authors.initials: E
authors.lastname: Lopez-Lopez
authors.forename: Javier
authors.initials: J
authors.lastname: Ballesteros
authors.forename: Maria A
authors.initials: MA
authors.lastname: Piñan
authors.forename: José
authors.initials: J
authors.lastname: Sanchez de Toledo
authors.forename: Nagore
authors.initials: N
authors.lastname: Garcia de Andoin
authors.forename: Purificacion
authors.initials: P
authors.lastname: Garcia-Miguel
authors.forename: Aurora
authors.initials: A
authors.lastname: Navajas
authors.forename: Africa
authors.initials: A
authors.lastname: Garcia-Orad
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000097:blood; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000097:blood; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: C000715087:ABCC2 protein, human; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D008727:Methotrexate