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Massive parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity

View ORCID ProfileChase C. Suiter, View ORCID ProfileTakaya Moriyama, View ORCID ProfileKenneth A. Matreyek, Wentao Yang, Emma Rose Scaletti, Rina Nishii, Wenjian Yang, View ORCID ProfileKeito Hoshitsuki, Minu Singh, View ORCID ProfileAmita Trehan, Chris Parish, Colton Smith, View ORCID ProfileDeepa Bhojwani, Liz YP Yuen, View ORCID ProfileChi-kong Li, Chak-ho Li, Yung-li Yang, Gareth J Walker, James R Goodhand, View ORCID ProfileNicholas A Kennedy, View ORCID ProfileFederico Antillon Klussmann, Smita Bhatia, Mary V. Relling, Motohiro Kato, Hiroki Hori, View ORCID ProfilePrateek Bhatia, Tariq Ahmad, Allen E. J. Yoeh, Pål Stenmark, View ORCID ProfileDouglas M. Fowler, Jun J. Yang
doi: https://doi.org/10.1101/740837
Chase C. Suiter
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Takaya Moriyama
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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  • ORCID record for Takaya Moriyama
Kenneth A. Matreyek
2Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Wentao Yang
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Emma Rose Scaletti
3Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, Sweden
4Department of Experimental Medical Science, Lund University, Lund, Sweden
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Rina Nishii
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Wenjian Yang
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Keito Hoshitsuki
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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  • ORCID record for Keito Hoshitsuki
Minu Singh
5Department of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India
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Amita Trehan
5Department of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India
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Chris Parish
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Colton Smith
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Deepa Bhojwani
6Department of Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, California, USA
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Liz YP Yuen
7Department of Pathology, Hong Kong Children’s Hospital, Hong Kong
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Chi-kong Li
8Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong
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Chak-ho Li
9Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Hong Kong
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Yung-li Yang
10Department of Laboratory Medicine and Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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Gareth J Walker
11Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England
12IBD Pharmacogenetics Group, University of Exeter, Exeter, England
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James R Goodhand
11Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England
12IBD Pharmacogenetics Group, University of Exeter, Exeter, England
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Nicholas A Kennedy
11Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England
12IBD Pharmacogenetics Group, University of Exeter, Exeter, England
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Federico Antillon Klussmann
13Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala, Francisco Marroquin Medical School, Guatemala City, Guatemala
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Smita Bhatia
14Division of Pediatric Hematology/Oncology, Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham
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Mary V. Relling
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Motohiro Kato
15Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan
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Hiroki Hori
16Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan
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Prateek Bhatia
5Department of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India
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Tariq Ahmad
11Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England
12IBD Pharmacogenetics Group, University of Exeter, Exeter, England
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Allen E. J. Yoeh
17Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
18Cancer Science Institute of Singapore, National University of Singapore, Singapore
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Pål Stenmark
3Department of Biochemistry and Biophysics, Arrhenius Laboratories for Natural Sciences, Stockholm University, Sweden
4Department of Experimental Medical Science, Lund University, Lund, Sweden
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Douglas M. Fowler
2Department of Genome Sciences, University of Washington, Seattle, WA, USA
19Department of Bioengineering, University of Washington, Seattle, WA, USA
20Genetic Networks Program, CIFAR, Toronto, ON, Canada
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Jun J. Yang
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
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  • For correspondence: jun.yang@stjude.org
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Abstract

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 novel genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction is quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine 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 2,398 patients treated with thiopurines, with 100% sensitivity and specificity, in contrast with poor performance of bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,103 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

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Posted August 20, 2019.
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Massive parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity
Chase C. Suiter, Takaya Moriyama, Kenneth A. Matreyek, Wentao Yang, Emma Rose Scaletti, Rina Nishii, Wenjian Yang, Keito Hoshitsuki, Minu Singh, Amita Trehan, Chris Parish, Colton Smith, Deepa Bhojwani, Liz YP Yuen, Chi-kong Li, Chak-ho Li, Yung-li Yang, Gareth J Walker, James R Goodhand, Nicholas A Kennedy, Federico Antillon Klussmann, Smita Bhatia, Mary V. Relling, Motohiro Kato, Hiroki Hori, Prateek Bhatia, Tariq Ahmad, Allen E. J. Yoeh, Pål Stenmark, Douglas M. Fowler, Jun J. Yang
bioRxiv 740837; doi: https://doi.org/10.1101/740837
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Massive parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity
Chase C. Suiter, Takaya Moriyama, Kenneth A. Matreyek, Wentao Yang, Emma Rose Scaletti, Rina Nishii, Wenjian Yang, Keito Hoshitsuki, Minu Singh, Amita Trehan, Chris Parish, Colton Smith, Deepa Bhojwani, Liz YP Yuen, Chi-kong Li, Chak-ho Li, Yung-li Yang, Gareth J Walker, James R Goodhand, Nicholas A Kennedy, Federico Antillon Klussmann, Smita Bhatia, Mary V. Relling, Motohiro Kato, Hiroki Hori, Prateek Bhatia, Tariq Ahmad, Allen E. J. Yoeh, Pål Stenmark, Douglas M. Fowler, Jun J. Yang
bioRxiv 740837; doi: https://doi.org/10.1101/740837

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