Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene

Objectives: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants. Design and methods: Restriction fragment length polymorphisin (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA. Results: In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1G>A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c. 1796T>C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17A>G. Conclusions: We report two new DPYD gene variants, of which DPYD c. 1796T>C is potentially pathogenic, whereas DPYD IVS14+17A>G is suggested as a variant without clinical significance. (C) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.