NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity

Autor: Matthias Schwab, Cesar R. Najera, Kjeld Schmiegelow, Zhiwei Chen, Cynthia Jeffries, Ching-Hon Pui, Mary V. Relling, Tomoya Isobe, Deepa Bhojwani, Allen Eng Juh Yeoh, Takaya Moriyama, Hiroki Hori, Atsushi Manabe, Keito Hoshitsuki, Yan Lu, Rina Nishii, Kentaro Kihira, Federico Antillon Klussmann, Robert McCorkle, Wenjian Yang, Jun J. Yang, Virginia Perez-Andreu, Hiroto Inaba, Katsuyoshi Koh, Lie Li, Shirley Kow-Yin Kham, Yoshihiro Komada, Xujie Zhao, Ting-Nien Lin, Motohiro Kato, Edwynn Kean Hui Chiew, Jacob Nersting, Ute Hofmann, William E. Evans
Rok vydání: 2016
Předmět:
Zdroj: Nature Genetics. 48:367-373
ISSN: 1546-1718
1061-4036
DOI: 10.1038/ng.3508
Popis: 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.
Databáze: OpenAIRE
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