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 (), the rate-limiting fluoropyrimidine metabolizing enzyme. In addition to SNVs, a study of Finnish patients suggested that a 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 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 gene, beyond fluoropyrimidine toxicity and show that various types of CNV in are present in the population. Taken together, our findings suggest that CNV in may be an underappreciated determinant of -mediated fluoropyrimidine toxicity.