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Clin Pharmacol Ther. 2018 Oct;104(4):709-718. doi: 10.1002/cpt.1020. Epub 2018 Feb 2.

Gene-Specific Variant Classifier (DPYD-Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase.

Author information

1
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
2
Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
3
Mayo Clinic Center for Individualized Medicine, Minnesota, USA.
4
Mayo Clinic Cancer Center, Rochester, Minnesota, USA.

Abstract

Deleterious variants in dihydropyrimidine dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. The developed model showed 85% accuracy and outperformed other in silico prediction tools. An examination of feature importance within the model provided additional insight into functional aspects of the DPD protein relevant to 5-FU toxicity. In the absence of clinical data for unstudied variants, prediction tools like DPYD-Varifier have great potential to individualize medicine and improve the clinical decision-making process.

PMID:
29327356
PMCID:
PMC6043412
[Available on 2019-10-01]
DOI:
10.1002/cpt.1020

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