Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity
Open accessAbstract
Significance: Pharmacogenetics is a prototype of genomics-guided precision medicine. While there is a rapid expansion of novel pharmacogenetic variants discovered by genome sequencing, the lack of variant interpretation in a scalable fashion is a formidable barrier in this field. NUDT15 polymorphism is a major genetic cause for hematopoietic toxicity during thiopurine therapy. Motivated by the need to understand NUDT15 variant effects for clinical actions, we developed a massively parallel assay to preemptively characterize 91.8% of all possible missense variants in NUDT15 . Our function-based variant classification accurately predicted thiopurine toxicity risk alleles in patients. These results vastly improved the ability to implement genotype-guided thiopurine therapy and illustrated the value and potential of a high-throughput variant effect screen in general.
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DMS strategies have previously been successfully employed to investigate functional relationships between small molecules and target proteins.
“Noteworthy, DMS strategies have previously been successfully employed to investigate functional relationships between small molecules and target proteins31,32.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [31]
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
Inference of macromolecular assemblies from crystalline state.
Krissinel, E., & Henrick, K. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.05.022 · Cited by 10,189 · see citing works
Adjusting batch effects in microarray expression data using empirical Bayes methods
Johnson, W. E., Li, C., & Rabinovic, A. (2007) · Biostatistics · doi:10.1093/biostatistics/kxj037 · Cited by 8,658 · see citing works
Self-citationA general framework for estimating the relative pathogenicity of human genetic variants
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014) · Nature Genetics · doi:10.1038/ng.2892 · Cited by 6,183 · see citing works
CADD: predicting the deleteriousness of variants throughout the human genome
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1016 · Cited by 3,534 · see citing works
ClinVar: public archive of relationships among sequence variation and human phenotype
Landrum, M. J., Lee, J. M., Riley, G. R., Jang, W., Rubinstein, W. S., Church, D. M., & Maglott, D. R. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1113 · Cited by 3,516 · see citing works
REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants
Ioannidis, N. M., Rothstein, J. H., Pejaver, V., Middha, S., McDonnell, S. K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.08.016 · Cited by 2,908 · see citing works
Accelerating t-SNE using tree-based algorithms
van der Maaten, L. (2014) · Journal of machine learning research · doi:10.5555/2627435.2697068 · Cited by 2,207 · see citing works
Evolution and functional impact of rare coding variation from deep sequencing of human exomes
Tennessen, J. A., Bigham, A. W., O’Connor, T. D., Fu, W., Kenny, E. E., Gravel, S., McGee, S., Do, R., Liu, X., Jun, G., et al. (2012) · Science · doi:10.1126/science.1219240 · Cited by 1,613 · see citing works
Accurate classification of BRCA1 variants with saturation genome editing
Findlay, G. M., Daza, R. M., Martin, B., Zhang, M. D., Leith, A. P., Gasperini, M., Janizek, J. D., Huang, X., Starita, L. M., & Shendure, J. (2018) · Nature · doi:10.1038/s41586-018-0461-z · Cited by 843 · see citing works
Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update
Pui, C., Carroll, W. L., Meshinchi, S., & Arceci, R. J. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.7405 · Cited by 840 · see citing works
Relling, M. V., Hancock, M. L., Rivera, G. K., Sandlund, J. T., Ribeiro, R. C., Krynetski, E. Y., Pui, C., & Evans, W. E. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.23.2001 · Cited by 731 · see citing works
Self-citationThe purine path to chemotherapy
Elion, G. B. (1989) · Science · doi:10.1126/science.2649979 · Cited by 687 · see citing works
Relling, M. V., Schwab, M. G., Whirl‐Carrillo, M., et al. (2018) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1304 · Cited by 687 · see citing works
Self-citationMutational processes shape the landscape of TP53 mutations in human cancer
Giacomelli, A. O., Yang, X., Lintner, R. E., McFarland, J. M., Duby, M., Kim, J., Howard, T. P., Takeda, D. Y., Ly, S. H., Kim, E., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0204-y · Cited by 556 · see citing works
A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia
Yang, S., Hong, M., Baek, J., Choi, H., Zhao, W., Jung, Y., Haritunians, T., Ye, B. D., Kim, K., Park, S. H., et al. (2014) · Nature Genetics · doi:10.1038/ng.3060 · Cited by 549 · see citing works
NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity
Moriyama, T., Nishii, R., Pérez-Andreu, V., Yang, W., Antillón‐Klussmann, F., Zhao, X., Lin, T.-N., Hoshitsuki, K., Nersting, J., Kihira, K., et al. (2016) · Nature Genetics · doi:10.1038/ng.3508 · Cited by 478 · see citing works
Self-citationKarran, P., & Attard, N. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2292 · Cited by 477 · see citing works
Vora, A. J., Goulden, N. J., Wade, R. L., Mitchell, C., Hancock, J. P., Hough, R. E., Rowntree, C. J., & Richards, S. M. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70600-9 · Cited by 476 · see citing works
Yang, J. J. J., Landier, W., Yang, W., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.4671 · Cited by 445 · see citing works
Self-citationMultiplex assessment of protein variant abundance by massively parallel sequencing
Matreyek, K. A., Starita, L. M., Stephany, J. J., Martin, B., Chiasson, M. A., Gray, V. E., Kircher, M., Khechaduri, A., Dines, J. N., Hause, R. J., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0122-z · Cited by 436 · see citing works
Self-citationRole of Postreplicative DNA Mismatch Repair in the Cytotoxic Action of Thioguanine
SWANN, P. F., Waters, T. R., Moulton, D. C., Xu, Y., Zheng, Q., Edwards, M., & Mace, R. (1996) · Science · doi:10.1126/science.273.5278.1109 · Cited by 409 · see citing works
Variant interpretation: functional assays to the rescue
Starita, L. M., Ahituv, N., Dunham, M. J., Kitzman, J. O., Roth, F. P., Seelig, G., Shendure, J., & Fowler, D. M. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.07.014 · Cited by 381 · see citing works
Self-citationCkmeans.1d.dp: Optimal k-means Clustering in One Dimension by Dynamic Programming
Wang, H., & Song, M. J. (2011) · The R Journal · doi:10.32614/rj-2011-015 · Cited by 367 · see citing works
Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL
Tzoneva, G., Pérez-García, A., Carpenter, Z., Khiabanian, H., Tosello, V., Allegretta, M., Paietta, E. M., Racevskis, J., Rowe, J. M., Tallman, M. S., et al. (2013) · Nature Medicine · doi:10.1038/nm.3078 · Cited by 350 · see citing works
Krynetski, E. Y., Schuetz, J. D., Galpin, A. J., et al. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.4.949 · Cited by 309 · see citing works
Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia
Meyer, J. A., Wang, J., Hogan, L. E., Yang, J. J. J., Dandekar, S. C., Patel, J. P., Tang, Z., Zumbo, P., Li, S., Zavadil, J., et al. (2013) · Nature Genetics · doi:10.1038/ng.2558 · Cited by 296 · see citing works
Self-citationEvaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines
Ghosh, R., Oak, N., & Plon, S. E. (2017) · Genome biology · doi:10.1186/s13059-017-1353-5 · Cited by 233 · see citing works
Azathioprine: old drug, new actions
Maltzman, J. S., & Koretzky, G. A. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18384 · Cited by 199 · see citing works
Negative feedback–defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL
Li, B., Li, H., Bai, Y., Kirschner‐Schwabe, R., Yang, J. J. J., Chen, Y., Lü, G., Tzoneva, G., Ma, X., Wu, T., et al. (2015) · Nature Medicine · doi:10.1038/nm.3840 · Cited by 175 · see citing works
Self-citationReinisch, W., Angelberger, S., Petritsch, W., et al. (2010) · Gut · doi:10.1136/gut.2009.194159 · Cited by 172 · see citing works
Walker, G., Harrison, J., Heap, G., Voskuil, M. D., Andersen, V. C., Anderson, C. A., Ananthakrishnan, A. N., Barrett, J. C., Beaugerie, L., Bewshea, C., et al. (2019) · JAMA · doi:10.1001/jama.2019.0709 · Cited by 171 · see citing works
Self-citationA comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family
Puigvert, J. C., Žitnik, M., Jemth, A., Carter, M., Unterlass, J. E., Hallström, B. M., Loseva, O., Karem, Z., Calderón‐Montaño, J. M., Lindskog, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01642-w · Cited by 170 · see citing works
Self-citationThe purine path to chemotherapy
Elion, G. B. (1989) · Bioscience Reports · doi:10.1007/bf01119794 · Cited by 166 · see citing works
The role of mismatch repair in DNA damage-induced apoptosis.
Li, G. (1999) · PubMed · Cited by 158 · see citing works
A platform for functional assessment of large variant libraries in mammalian cells
Matreyek, K. A., Stephany, J. J., & Fowler, D. M. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx183 · Cited by 140 · see citing works
Self-citationExpression of the MutL Homologue hMLH3 in Human Cells and its Role in DNA Mismatch Repair
Cannavò, E., Marra, G., Sabates–Bellver, J., Menigatti, M., Lipkin, S. M., Fischer, F., Ćejka, P., & Jiricny, J. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2528 · Cited by 125 · see citing works
Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD
de Boer, N. K. H., van Bodegraven, A. A., Jharap, B., et al. (2007) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep1000 · Cited by 125 · see citing works
NUDT15 Hydrolyzes 6-Thio-DeoxyGTP to Mediate the Anticancer Efficacy of 6-Thioguanine
Valerie, N. C. K., Hagenkort, A., Page, B. D. G., Masuyer, G., Rehling, D., Carter, M., Bevc, L., Herr, P., Homan, E. J., Gustafsson, N., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0584 · Cited by 122 · see citing works
Self-citationCarter, M., Jemth, A., Hagenkort, A., Page, B. D. G., Gustafsson, R., Griese, J. J., Gad, H., Valerie, N. C. K., Desroses, M., Boström, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms8871 · Cited by 116 · see citing works
Self-citationMoriyama, T., Yang, Y., Nishii, R., Ariffin, H., Liu, C., Lin, T.-N., Yang, W., Lin, D., Yu, C., Kham, S. K. Y., et al. (2017) · Blood · doi:10.1182/blood-2017-05-782383 · Cited by 108 · see citing works
Self-citationHuman MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates
Takagi, Y., Setoyama, D., Ito, R., Kamiya, H., Yamagata, Y., & Sekiguchi, M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.363010 · Cited by 105 · see citing works
Moriyama, T., Nishii, R., Lin, T.-N., Kihira, K., Toyoda, H., Nersting, J., Kato, M., Koh, K., Inaba, H., Manabe, A., et al. (2017) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0000000000000282 · Cited by 74 · see citing works
Self-citationPharmacogene Variation Consortium Gene Introduction: NUDT15
Yang, J. J. J., Whirl‐Carrillo, M., Scott, S. A., et al. (2018) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1268 · Cited by 59 · see citing works
Self-citationLf, J., Eichelbaum, M., Griese, E.-U., Inaba, T., & Td, A. (1999) · PubMed · Cited by 53 · see citing works
Toxicity and response to thiopurines in patients with inflammatory bowel disease
Goldberg, R., & Irving, P. M. (2015) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/17474124.2015.1039987 · Cited by 46 · see citing works
Yoshida, S., Yamada, M., Masaki, S., & Saneyoshi, M. (1979) · PubMed · Cited by 40 · see citing works
Ling, Y.-H., Nelson, J. A., Cheng, Y., Anderson, R. S., & Beattie, K. L. (1991) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)15361-3 · Cited by 31 · see citing works
ABSSeq: a new RNA-Seq analysis method based on modelling absolute expression differences
Yang, W., Rosenstiel, P. C., & Schulenburg, H. (2016) · BMC Genomics · doi:10.1186/s12864-016-2848-2 · Cited by 26 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Rapid protein stability prediction using deep learning representations
Blaabjerg, L. M., Kassem, M. M., Good, L. L., Jonsson, N., Cagiada, M., Johansson, K. E., Boomsma, W., Stein, A., & Lindorff-Larsen, K. (2023) · eLife · doi:10.7554/elife.82593 · Cited by 177 · see citing works
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Hanzl, A., Casement, R., Imrichova, H., Hughes, S. J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01177-2 · Cited by 133 · see citing works
McInnes, G., Sharo, A. G., Koleske, M. L., Brown, J. E. H., Norstad, M., Adhikari, A. N., Wang, S., Brenner, S. E., Halpern, J., Koenig, B. A., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.03.003 · Cited by 86 · see citing works
“The American Journal of Human Genetics 108 , 535–548, April 1, 2021 537 include enzyme activity assays 23 and transporter uptake assays.”
Method<scp>ESM</scp> ‐scan—A tool to guide amino acid substitutions
Totaro, M. G., Vide, U., Zausinger, R., Winkler, A., & Oberdorfer, G. (2024) · Protein Science · doi:10.1002/pro.5221 · Cited by 19 · see citing works
Zhong, G., Zhao, Y., Zhuang, D., Chung, W. K., & Shen, Y. (2025) · Nature Communications · doi:10.1038/s41467-025-62318-4 · Cited by 15 · see citing works
- Authors
- Suiter, C. C., Moriyama, T., Matreyek, K. A., Yang, W., Scaletti, E. R., Nishii, R., Yang, W., Hoshitsuki, K., Singh, M., Trehan, A., Parish, C., Smith, C., Li, L., Bhojwani, D., Yuen, L. Y. P., Li, C.-K., Li, C.-H., Yang, Y.-L., Walker, G. J., Goodhand, J. R., Kennedy, N. A., Klussmann, F. A., Bhatia, S., Relling, M. V., Kato, M., Hori, H., Bhatia, P., Ahmad, T., Yeoh, A. E. J., Stenmark, P., Fowler, D. M., & Yang, J. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Washington (US)
- Stockholm University (SE)
- Post Graduate Institute of Medical Education and Research (IN)
- Children's Hospital Los Angeles (US)
- Hong Kong Children's Hospital (HK)
- Chinese University of Hong Kong (HK)
- National Taiwan University (TW)
- University of Exeter (GB)
- Unidad Nacional de Oncología Pediátrica, Guatemala City 01011, Guatemala;
- University of Alabama (US)
- National Center For Child Health and Development (JP)
- Mie University (JP)
- National University of Singapore (SG)
- Canadian Institute for Advanced Research (CA)
- ORCID
- Suiter, Chase C.
- Moriyama, Takaya
- Matreyek, Kenneth A.
- Yang, Wentao
- Scaletti, Emma Rose
- Yang, Wenjian
- Hoshitsuki, Keito
- Singh, Minu
- Trehan, Amita
- Smith, Colton
- Li, Lie
- Bhojwani, Deepa
- Li, Chi-kong
- Yang, Yung-li
- Walker, Gareth J.
- Goodhand, James R.
- Kennedy, Nicholas A.
- Bhatia, Smita
- Relling, Mary V.
- Kato, Motohiro
- Hori, Hiroki
- Bhatia, Prateek
- Ahmad, Tariq
- Yeoh, Allen E. J.
- Stenmark, Pål
- Fowler, Douglas M.
- Yang, Jun J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-02-24
- Volume
- 117
- Issue
- 10
- Pages
- 5394-5401
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7071893
- OpenAlex
- W3008294336
- Cited by
- 121
- References
- 49
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 21 · 2023: 20 · 2022: 19 · 2021: 24 · 2020: 10 · 2019: 1
- FWCI
- 16.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- HHS | National Institutes of Health (CA021765, GM115279, GM118578, R01CA096670)
- V Foundation for Cancer Research (T2015-006)
- Alex's Lemonade Stand Foundation for Childhood Cancer (17-00560)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- NUDT15, thiopurine toxicity, pharmacogenetics, missense mutations, variant effect prediction, hematopoietic toxicity, genotype-guided therapy, precision medicine
- MeSH terms
- Pharmacogenomic Variants, Protein Conformation, alpha-Helical, Nudix Hydrolases, Alleles, Antimetabolites, Dose-Response Relationship, Drug, Enzyme Stability, Humans, Pyrophosphatases, Risk, Mercaptopurine, Amino Acid Substitution, Mutation, Missense, Endpoint Determination, Precision Medicine, HEK293 Cells
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