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

Curr Oncol. 2023 Jan 4;30(1):663-672. doi: 10.3390/curroncol30010051.

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.

Keywords: adverse drug reactions; copy number variation; dihydropyrimidine dehydrogenase deficiency; fluoropyrimidines; pharmacogenetics.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Canada
  • Capecitabine / adverse effects
  • DNA Copy Number Variations
  • Dihydrouracil Dehydrogenase (NADP)* / genetics
  • Exons
  • Fluorouracil* / adverse effects
  • Humans

Substances

  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil
  • Capecitabine

Grants and funding

This work was funded by the Ontario Institute of Cancer Research Pre-CATA (P.CTP.725), Ontario Research Fund – Research Excellence (RE08–063), T.J.W. is supported by an Ontario Graduate Scholarship and R.B.K. holds the Wolfe Medical Research Chair in Pharmacogenomics.