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The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.

ABSTRACT: Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.

SUBMITTER: Moriyama T

PROVIDER: S-EPMC5510236 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.

Moriyama Takaya T Nishii Rina R Lin Ting-Nien TN Kihira Kentaro K Toyoda Hidemi H Jacob Nersting N Kato Motohiro M Koh Katsuyoshi K Inaba Hiroto H Manabe Atsushi A Schmiegelow Kjeld K Yang Jun J JJ Hori Hiroki H

Pharmacogenetics and genomics 20170601 6

Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabo ...[more]

PMID: 28445187

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Project description:Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA, both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT, NUDT15, and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

Dataset Information

The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.

Publications

The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia.

Similar Datasets

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