Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity.

Autor:	Suiter CC; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Moriyama T; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Matreyek KA; Department of Genome Sciences, University of Washington, Seattle, WA 98195., Yang W; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Scaletti ER; Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden.; Department of Experimental Medical Science,Lund University, 221 00 Lund, Sweden., Nishii R; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Yang W; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Hoshitsuki K; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Singh M; Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education & Research, 160012 Chandigarh, India., Trehan A; Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education & Research, 160012 Chandigarh, India., Parish C; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Smith C; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Li L; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Bhojwani D; Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, CA 90027., Yuen LYP; Department of Pathology, Hong Kong Children's Hospital, Hong Kong., Li CK; Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong., Li CH; Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong., Yang YL; Department of Laboratory Medicine and Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10617, Taiwan., Walker GJ; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter EX2 5DW, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter EX2 5DW, England., Goodhand JR; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter EX2 5DW, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter EX2 5DW, England., Kennedy NA; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter EX2 5DW, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter EX2 5DW, England., Klussmann FA; Unidad Nacional de Oncología Pediátrica, Guatemala City 01011, Guatemala.; Department of Pediatrics, Francisco Marroquin Medical School, Guatemala City 01011, Guatemala., Bhatia S; Division of Pediatric Hematology/Oncology, Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama, Birmingham, AL 35294., Relling MV; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105., Kato M; Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo 157-8535, Japan., Hori H; Department of Pediatrics, Mie University Graduate School of Medicine, Mie 514-8507, Japan., Bhatia P; Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education & Research, 160012 Chandigarh, India., Ahmad T; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter EX2 5DW, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter EX2 5DW, England., Yeoh AEJ; Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599.; Cancer Science Institute of Singapore, National University of Singapore, Singapore 117597., Stenmark P; Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden.; Department of Experimental Medical Science,Lund University, 221 00 Lund, Sweden., Fowler DM; Department of Genome Sciences, University of Washington, Seattle, WA 98195.; Department of Bioengineering, University of Washington, Seattle, WA 98195.; Genetic Networks Program, CIFAR, Toronto, ON M5G 1M1, Canada., Yang JJ; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105; jun.yang@stjude.org.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 10; Vol. 117 (10), pp. 5394-5401. Date of Electronic Publication: 2020 Feb 24.
DOI:	10.1073/pnas.1915680117
Abstrakt:	As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15 -informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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