Genetic variants of the NUDT15 gene drive toxicity in leukemia therapy

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 thiopurine (for example, 6-mercaptopurine) treatment, not just for acute lymphoblastic leukemia (ALL) but for other diseases treated with thiopurines, such as inflammatory bowel disease, 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: