NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.

Autor: Moriyama T; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan., Nishii R; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan., Perez-Andreu V; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Yang W; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Klussmann FA; Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala.; Francisco Marroquin Medical School, Guatemala City, Guatemala., Zhao X; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Lin TN; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Hoshitsuki K; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.; School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Nersting J; Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark., Kihira K; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan., Hofmann U; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany., Komada Y; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan., Kato M; Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan., McCorkle R; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Li L; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Koh K; Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan., Najera CR; Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala., Kham SK; National University Cancer Institute, National University Health System, Singapore., Isobe T; Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan., Chen Z; National University Cancer Institute, National University Health System, Singapore., Chiew EK; National University Cancer Institute, National University Health System, Singapore., Bhojwani D; Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA., Jeffries C; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Lu Y; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Schwab M; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.; Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.; German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany., Inaba H; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Pui CH; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Relling MV; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Manabe A; Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan., Hori H; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan., Schmiegelow K; Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Yeoh AE; National University Cancer Institute, National University Health System, Singapore.; Viva University Children's Cancer Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Evans WE; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Yang JJ; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2016 Apr; Vol. 48 (4), pp. 367-73. Date of Electronic Publication: 2016 Feb 15.
DOI: 10.1038/ng.3508
Abstrakt: Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.
Competing Interests: Statement The authors have no competing financial interest to disclose.
Databáze: MEDLINE
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