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

Authors :
Theodore J. Wigle
Samantha Medwid
Cameron Ross
Ute I. Schwarz
Richard B. Kim
Source :
Current Oncology, Vol 30, Iss 1, Pp 663-672 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

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.

Details

Language :
English
ISSN :
17187729 and 11980052
Volume :
30
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Current Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.525f99bb3b456bbd09e2b8d9d5124c
Document Type :
article
Full Text :
https://doi.org/10.3390/curroncol30010051