Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency

Clin Cancer Res. 2001 May;7(5):1149-53.

Abstract

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk from developing a severe 5FU-associated toxicity. In this study, we demonstrated that a lethal toxicity after a treatment with 5FU was attributable to a complete deficiency of DPD. Analysis of the DPD gene for the presence of mutations showed that the patient was homozygous for a G-->A mutation in the invariant GT splice donor site flanking exon 14 (IVS14+1G>A). As a consequence, no significant residual activity of DPD was detected in peripheral blood mononuclear cells. To determine the frequency of the IVS14+1G>A mutation in the Dutch population, we developed a novel PCR-based method allowing the rapid analysis of the IVS14+1G>A mutation by RFLP. Screening for the presence of this mutation in 1357 Caucasians showed an allele frequency of 0.91%. In our view, the apparently high prevalence of the IVS14+1G>A mutation in the normal population, with 1.8% heterozygotes, warrants genetic screening for the presence of this mutation in cancer patients before the administration of 5FU.

Publication types

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

MeSH terms

  • Adult
  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / toxicity*
  • Dihydrouracil Dehydrogenase (NADP)
  • Exons / genetics
  • Fatal Outcome
  • Female
  • Fibroblasts / enzymology
  • Fluorouracil / metabolism
  • Fluorouracil / toxicity*
  • Gene Frequency
  • Humans
  • Leukocytes, Mononuclear / enzymology
  • Mutation
  • Oxidoreductases / deficiency
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Polymorphism, Restriction Fragment Length
  • Thymine / blood
  • Uracil / blood

Substances

  • Antimetabolites, Antineoplastic
  • Uracil
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymine
  • Fluorouracil