title: Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.
abstract: OBJECTIVE
  In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation.
  
  
  METHODS
  We measured TPMT (activity, as units ml(-1) packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8 × 10(8) RBCs) during chemotherapy (n = 1131) in children randomized to thioguanine or mercaptopurine on the United Kingdom trial ALL97.
  
  
  RESULTS
  Median TPMT activity at diagnosis (8.5 units) was significantly lower than during chemotherapy (13.8 units, median difference 5.1 units, 95% confidence interval (CI) 4.8, 5.4, P < 0.0001). At diagnosis genotype-phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754 pmol) than wild-type (360 pmol) patients (median difference 406 pmol, 95% CI 332, 478, P < 0.0001), whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10 650 pmol) than heterozygous patients (3868 pmol) (P < 0.0001). In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366 pmol) and MeMPN (median 8590 pmol) concentrations were similar to those in wild-type, high activity patients.
  
  
  CONCLUSIONS
  In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy.
authors.affiliation: Clinical Pharmacology Unit, Department of Human Metabolism, University of Sheffield, Sheffield, UK. l.lennard@sheffield.ac.uk
authors.forename: Lynne
authors.initials: L
authors.lastname: Lennard
authors.forename: Cher Suzanne
authors.initials: CS
authors.lastname: Cartwright
authors.forename: Rachel
authors.initials: R
authors.lastname: Wade
authors.forename: Susan M
authors.initials: SM
authors.lastname: Richards
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000097:blood; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013866:Thioguanine / Q000378:metabolism / Q000627:therapeutic use*; D013873:Thionucleotides / Q000097:blood; D006113:United Kingdom
chemical_list: D000964:Antimetabolites, Antineoplastic; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine