Dihydropyrimidine Dehydrogenase Deficiency in Patients with Severe Toxicity After 5-fluorouracil: a Retrospective Single-center Study

Background: 5-Fluorouracil (5-FU) is an agent frequently used in the treatment of solid cancers. A deficiency in the enzyme that catabolizes 5-FU leads to severe toxicity. The gene responsible for this enzyme is , located on chromosome 1q22. The most prevalent alteration described is , which leads to a splicing defect and thus skipping of the translation of an entire exon. The objectives of this retrospective study were to describe the frequencies of gene mutations in a Belgian population and to correlate them with the grade of toxicity.

Methods: This was a retrospective, single-center study conducted at the University Hospitals Leuven, by reviewing a database of patients screened for gene mutations between May 2009 and June 2015 after prolonged grade 3-4 toxicity. Polymerase chain reaction sequencing of exons 2, 6, 10, 11, 13, 18, 19 and 22, and pyrosequencing of exon 14 were performed by an in-house laboratory.

Results: Of the 80 patients screened, 65 were heterozygous or compound heterozygous for and 3 had a homozygous mutation. The most prevalent mutation in our population was .

Conclusions: Despite previous reports, in our small retrospective study the most prevalent variation in patients with severe adverse events was . As this variant has previously been reported to be benign, we suggest that screening for dihydropyrimidine dehydrogenase deficiency should be extended across multiple exons of the gene.