Journal
NATURE GENETICS
Volume 48, Issue 4, Pages 367-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3508
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Funding
- US National Institutes of Health [CA021765, GM115279]
- American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital
- Order of St. Francis Foundation
- V Foundation for Cancer Research
- Danish Childhood Cancer Foundation
- Japanese Ministry of Health
- National Medical Research Council (Singapore)
- Children's Cancer Foundation
- Viva Foundation for Children with Cancer
- Mie Prefecture Study-Abroad Scholarship (Mie, Japan)
- Robert Bosch Foundation (Stuttgart, Germany)
- Pediatric Oncology Education Program [CA23944]
- Alex's Lemonade Stand Foundation
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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 x 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 x 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.
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