Genetic variants of the NUDT15 gene drive toxicity in leukemia therapy

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February 27, 2020 – Thiopurines are important antimetabolite drugs, which make up a critical part of curative treatment for ALL. Genetic variations can directly influence drug and effectiveness of thiopurines. Researchers at St. Jude and elsewhere previously identified NUDT15 variants as a major genetic cause of toxicity during thiopurine therapy, particularly in people of Asian and Hispanic descent.

Scientists at St. Jude Children’s Research Hospital, alongside collaborators around the world, have created a comprehensive reference of functional variants in an important drug-metabolizing enzyme called NUDT15. This thorough understanding of NUDT15 variants provides an invaluable resource for predicting which patients being treated with thiopurine drugs for acute lymphoblastic leukemia (ALL) are likely to experience toxicity. The work was published today in the Proceedings of the National Academy of Science (PNAS).

Generally, pharmacogenetics uses genomic data to guide precision medicine. To implement genetic-guided treatment, researchers and physicians need a rigorous and thorough understanding of all the genetic variants of each gene concerned and their relative functions, respectively, in order to understand what clinical phenotypes they stand for. The vast majority of genetic variants, even those of a single gene, in the human genome remain uncharacterized. Unfortunately, to these days, these variants (many of them very rare in the population) are considered of unknown significance, leaving a void in our knowledge about how to implement precision medicine, including pharmacogenetics, for those patients carrying such variants.

To address this issue, a high throughput experimental system was designed to characterize the functional consequences of 91% of all possible genetic variants of the NUDT15 gene, according to the team of researchers behind the current study. In the span of only a few months, thy experimentally studied close to 3,000 variants in the NUTD15 gene in parallel and found that 30% of the found variants are damaging, i.e., are predicted to cause thiopurine toxicity in patients.

Variants identified in this way (by function) more accurately predict toxicity in patients treated with thiopurines than bioinformatic algorithms can. Using patient data with a subset of these variants, the researchers found that NUDT15 variants predicted by this method to cause toxicity, did induce such toxicity. Conversely, the variants predicted to have benign effects did not cause toxicity. While the authors caution that future studies of still larger sample sizes are needed to validate these results, the initial findings show promise.

This reference vastly improves the ability to implement pharmacogenetics-guided  (for example, 6-mercaptopurine) treatment, not just for acute lymphoblastic leukemia (ALL) but for other diseases treated with thiopurines, such as , as well. We need to understand that the scale of this type of variant-scanning experiment was almost unimaginable just a couple of years ago. It is real progress to be able to apply in the study many other genes related to drug response also in oder to elucidate rather precise therapy option for many many patients in the future.

See here a short sequence on the many aspects (genetic and other) of thiopurine therapies:

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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