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Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.

ABSTRACT: 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.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.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.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.

SUBMITTER: Lennard L

PROVIDER: S-EPMC3703235 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.

Lennard Lynne L Cartwright Cher Suzanne CS Wade Rachel R Richards Susan M SM Vora Ajay A

British journal of clinical pharmacology 20130701 1

<h4>Aims</h4>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.<h4>Methods</h4>We measured TPMT (activity, as units ml(-1) packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide ( ...[more]

PMID: 23252716

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Project description:PurposeInvestigate in vivo cone photoreceptor structure in familial aniridia caused by deletion in the PAX6 gene to elucidate the complexity of between-individual variation in retinal phenotype.DesignDescriptive case-control study.ParticipantsEight persons with congenital aniridia (40-66 yrs) from 1 family and 33 normal control participants (14-69 yrs), including 7 unaffected family members (14-53 yrs).MethodsDNA was isolated from saliva samples and used in polymerase chain reaction analysis to amplify and sequence exons and intron or exon junctions of the PAX6 gene. High-resolution retinal images were acquired with OCT and adaptive optics scanning light ophthalmoscopy. Cone density (CD; in cones per square millimeter) and mosaic regularity were estimated along nasal-temporal meridians within the central 0° to 5° eccentricity. Horizontal spectral-domain OCT line scans were segmented to analyze the severity of foveal hypoplasia (FH) and to measure retinal layer thicknesses.Main outcomes and measuresWithin-family variability in macular retinal layer thicknesses, cone photoreceptor density, and mosaic regularity in aniridia compared with normal control participants.ResultsDNA sequencing revealed a known PAX6 mutation (IV2-2delA). Those with aniridia showed variable iris phenotype ranging from almost normal appearance to no iris. Four participants with aniridia demonstrated FH grade 2, 2 demonstrated grade 3 FH, and 1 demonstrated grade 4 FH. Visual acuity ranged from 0.20 to 0.86 logarithm of the minimum angle of resolution. Adaptive optics scanning light ophthalmoscopy images were acquired from 5 family members with aniridia. Foveal CD varied between 19 899 and 55 128 cones/mm2 with overlap between the foveal hypoplasia grades. Cone density was 3 standard deviations (SDs) or more less than the normal mean within 0.5°, 2 SDs less than the normal mean at 0.5° to 4°, and more than 1 SD less than the normal mean at 5° retinal eccentricity.ConclusionsThe results showed considerable variability in foveal development within a family carrying the same PAX6 mutation. This, together with the structural and functional variability within each grade of foveal hypoplasia, underlines the importance of advancing knowledge about retinal cellular phenotype in aniridia.

Dataset Information

Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.

Publications

Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.

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