title: Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia.
abstract: Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P = .02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms.
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Ansari
authors.forename: Géraldine
authors.initials: G
authors.lastname: Sauty
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Labuda
authors.forename: Vincent
authors.initials: V
authors.lastname: Gagné
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.forename: Albert
authors.initials: A
authors.lastname: Moghrabi
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Maja
authors.initials: M
authors.lastname: Krajinovic
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use; D008727:Methotrexate / Q000627:therapeutic use; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C073492:ABCC4 protein, human