Document Type
Article
Publication Date
11-2026
Identifier
DOI: 10.1002/cpt.70433; PMCID: PMC13446156
Abstract
The Clinical Pharmacogenetics Implementation Consortium (CPIC) TPMT/NUDT15 Pharmacogene Curation Expert Panel (PCEP) conducted a comprehensive review of clinical, laboratory, and computational evidence to determine the clinical function assignments for TPMT and NUDT15 star alleles. These genes are critical for the metabolism of thiopurines, which are widely used in the treatment of cancer and autoimmune disorders. Standardized allele function assignment is essential for predicting metabolizer phenotypes and pharmacogenetics-guided thiopurine dosing. The work presented here includes the first designation of decreased function alleles for both TPMT and NUDT15, reflecting new clinical data that demonstrate partial loss of enzymatic activity and reduced dose tolerance. The panel also reclassified several alleles previously assigned uncertain or unknown function. The functional assignments were informed by a standardized framework incorporating clinical data, such as thiopurine tolerance and toxicity, as well as in vitro protein activity, ex vivo enzymatic measurements, and in silico variant effect prediction tools. These updates enhance the precision of genotype-to-phenotype mapping and support more personalized thiopurine therapy across diverse patient populations.
Journal Title
Clinical pharmacology and therapeutics
Volume
120
Issue
5
First Page
1427
Last Page
1437
MeSH Keywords
Humans; Nudix Hydrolases; Methyltransferases; Pyrophosphatases; Pharmacogenetics; Alleles; Phenotype; Mercaptopurine
PubMed ID
42560154
Keywords
Nudix Hydrolases; Methyltransferases; Pyrophosphatases; Pharmacogenetics; Alleles; Phenotype; Mercaptopurine
Recommended Citation
Tibben BM, Maillard M, Pratt VM, et al. Clinical Functional Assignment of TPMT and NUDT15 Alleles by the Clinical Pharmacogenetics Implementation Consortium Pharmacogene Curation Expert Panel. Clin Pharmacol Ther. 2026;120(5):1427-1437. doi:10.1002/cpt.70433
Comments
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Publisher's Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.70433