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

Shikshya Shrestha; Cheng Zhang; Calvin R. Jerde; Qian Nie; Hu Li; Steven M. Offer; Robert B. Diasio

doi:10.1002/cpt.1020

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

Journal article

Peer reviewed

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

Shikshya Shrestha, Cheng Zhang, Calvin R. Jerde, Qian Nie, Hu Li, Steven M. Offer and Robert B. Diasio

Clinical pharmacology and therapeutics, Vol.104(4), pp.709-718

10/2018

DOI: 10.1002/cpt.1020

PMCID: PMC6043412

PMID: 29327356

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https://www.ncbi.nlm.nih.gov/pmc/articles/6043412View

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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.

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: Gene-Specific Variant Classifier (DPYD-Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase
Creators: Shikshya Shrestha - Mayo Clinic
Cheng Zhang - Mayo Clinic
Calvin R. Jerde - Mayo Clinic
Qian Nie - Mayo Clinic
Hu Li - Mayo Clinic
Steven M. Offer - Mayo Clinic
Robert B. Diasio - Mayo Clinic
Resource Type: Journal article
Publication Details: Clinical pharmacology and therapeutics, Vol.104(4), pp.709-718
DOI: 10.1002/cpt.1020
PMID: 29327356
PMCID: PMC6043412
NLM abbreviation: Clin Pharmacol Ther
ISSN: 0009-9236
eISSN: 1532-6535
Publisher: Wiley
Number of pages: 10
Grant note: P30 CA15083 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA015083 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
Language: English
Date published: 10/2018
Academic Unit: Pathology
Record Identifier: 9984618650402771

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