title: Clinical impact of ABCC1 and ABCC2 genotypes and haplotypes in mediating imatinib resistance among chronic myeloid leukaemia patients.
abstract: OBJECTIVE
  The introduction and success of imatinib mesylate (IM) has brought about a paradigm shift in chronic myeloid leukaemia (CML) treatment. However, despite the high efficacy of IM, clinical resistance develops due to a heterogeneous array of mechanisms. Pharmacogenetic variability as a result of genetic polymorphisms could be one of the most important factors influencing resistance to IM. The aim of this study was to investigate the association between genetic variations in drug efflux transporter ABCC1 (MRP1) and ABCC2 (MRP2) genes and response to IM in patients with CML.
  
  
  METHODS
  We genotyped 215 Malaysian patients with CML (comprising of two groups with 108 IM resistant and 107 IM responsive) for polymorphisms of ABCC1 (2012G>T and 2168G>A) and ABCC2 (-24C>T, 1249G>A and 3972C>T) genes. Genotype, allele and haplotype frequencies were compared between two groups of patients. Patients with CML were further stratified according to their clinical response to IM into those having cytogenetics and molecular responses, and the associations with genotypes were evaluated.
  
  
  CONCLUSIONS
  We observed no significant differences in the distribution of any of the tested genotypes between the investigated groups. However, on evaluating the risk association, ABCC2 T₋₂₄ G₁₂₄₉ T₃₉₇₂ haplotype was found to be associated with IM resistance (P = 0·046). These results suggest that haplotype variants -24T and 3972T might be associated with lower expression of ABCC2 protein and reduced transport activity and hence might be contributing to development of IM resistance.
  
  
  CONCLUSIONS
  Our results suggest the ABCC2 T₋₂₄ G₁₂₄₉ T₃₉₇₂ haplotype was associated with imatinib resistance. However, the evidence is as yet insufficient to establish this haplotype as a predictive biomarker for response to the drug.
authors: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
authors: A
authors: A
authors: Au
authors: A A
authors: AA
authors: Baba
authors: H
authors: H
authors: Azlan
authors: B
authors: B
authors: Norsa'adah
authors: R
authors: R
authors: Ankathil
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D001549:Benzamides / Q000627:therapeutic use*; D002648:Child; D003430:Cross-Sectional Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000068877:Imatinib Mesylate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; D011743:Pyrimidines; C000715087:ABCC2 protein, human; C421109:multidrug resistance-associated protein 1
keywords: ABCC1; ABCC2; chronic myeloid leukaemia; genetic polymorphisms; imatinib resistance