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DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation

Fluoropyrimidine chemotherapy is associated with interpatient variability in toxicity. A major contributor to unpredictable and severe toxicity relates to single nucleotide variation (SNV) in dihydropyrimidine dehydrogenase (DPYD), the rate-limiting fluoropyrimidine metabolizing enzyme. In addition...

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Autores principales: Wigle, Theodore J., Medwid, Samantha, Ross, Cameron, Schwarz, Ute I., Kim, Richard B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9857685/
https://www.ncbi.nlm.nih.gov/pubmed/36661700
http://dx.doi.org/10.3390/curroncol30010051
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author Wigle, Theodore J.
Medwid, Samantha
Ross, Cameron
Schwarz, Ute I.
Kim, Richard B.
author_facet Wigle, Theodore J.
Medwid, Samantha
Ross, Cameron
Schwarz, Ute I.
Kim, Richard B.
author_sort Wigle, Theodore J.
collection PubMed
description Fluoropyrimidine chemotherapy is associated with interpatient variability in toxicity. A major contributor to unpredictable and severe toxicity relates to single nucleotide variation (SNV) in dihydropyrimidine dehydrogenase (DPYD), the rate-limiting fluoropyrimidine metabolizing enzyme. In addition to SNVs, a study of Finnish patients suggested that a DPYD exon 4 deletion was observed in their population. To better understand the potential generalizability of such findings, we investigated the presence of this exon 4 deletion in our Canadian patient population, using a TaqMan assay. We selected 125 patients who experienced severe fluoropyrimidine-associated toxicity, and 125 matched controls. One patient in the severe toxicity group harbored a haploid DPYD exon 4 deletion, and required a 35% dose reduction after their first fluoropyrimidine treatment cycle due to toxicity and required an additional 30% dose reduction before tolerating treatment. The predicted allele frequency was 0.2% in our cohort, much lower than the 2.4% previously reported. We also carried out a literature review of copy number variation (CNV) in the DPYD gene, beyond fluoropyrimidine toxicity and show that various types of CNV in DPYD are present in the population. Taken together, our findings suggest that CNV in DPYD may be an underappreciated determinant of DPYD-mediated fluoropyrimidine toxicity.
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spelling pubmed-98576852023-01-21 DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation Wigle, Theodore J. Medwid, Samantha Ross, Cameron Schwarz, Ute I. Kim, Richard B. Curr Oncol Article Fluoropyrimidine chemotherapy is associated with interpatient variability in toxicity. A major contributor to unpredictable and severe toxicity relates to single nucleotide variation (SNV) in dihydropyrimidine dehydrogenase (DPYD), the rate-limiting fluoropyrimidine metabolizing enzyme. In addition to SNVs, a study of Finnish patients suggested that a DPYD exon 4 deletion was observed in their population. To better understand the potential generalizability of such findings, we investigated the presence of this exon 4 deletion in our Canadian patient population, using a TaqMan assay. We selected 125 patients who experienced severe fluoropyrimidine-associated toxicity, and 125 matched controls. One patient in the severe toxicity group harbored a haploid DPYD exon 4 deletion, and required a 35% dose reduction after their first fluoropyrimidine treatment cycle due to toxicity and required an additional 30% dose reduction before tolerating treatment. The predicted allele frequency was 0.2% in our cohort, much lower than the 2.4% previously reported. We also carried out a literature review of copy number variation (CNV) in the DPYD gene, beyond fluoropyrimidine toxicity and show that various types of CNV in DPYD are present in the population. Taken together, our findings suggest that CNV in DPYD may be an underappreciated determinant of DPYD-mediated fluoropyrimidine toxicity. MDPI 2023-01-04 /pmc/articles/PMC9857685/ /pubmed/36661700 http://dx.doi.org/10.3390/curroncol30010051 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wigle, Theodore J.
Medwid, Samantha
Ross, Cameron
Schwarz, Ute I.
Kim, Richard B.
DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation
title DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation
title_full DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation
title_fullStr DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation
title_full_unstemmed DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation
title_short DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation
title_sort dpyd exon 4 deletion associated with fluoropyrimidine toxicity and importance of copy number variation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9857685/
https://www.ncbi.nlm.nih.gov/pubmed/36661700
http://dx.doi.org/10.3390/curroncol30010051
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