Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1784873924645879808 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9857685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT wigletheodorej dpydexon4deletionassociatedwithfluoropyrimidinetoxicityandimportanceofcopynumbervariation AT medwidsamantha dpydexon4deletionassociatedwithfluoropyrimidinetoxicityandimportanceofcopynumbervariation AT rosscameron dpydexon4deletionassociatedwithfluoropyrimidinetoxicityandimportanceofcopynumbervariation AT schwarzutei dpydexon4deletionassociatedwithfluoropyrimidinetoxicityandimportanceofcopynumbervariation AT kimrichardb dpydexon4deletionassociatedwithfluoropyrimidinetoxicityandimportanceofcopynumbervariation |