title: 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.
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.
authors.affiliation: Emma Children's Hospital and Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands. a.b.vankuilenburg@amc.uva.nl
authors.forename: A B
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: E W
authors.initials: EW
authors.lastname: Muller
authors.forename: J
authors.initials: J
authors.lastname: Haasjes
authors.forename: R
authors.initials: R
authors.lastname: Meinsma
authors.forename: L
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: H R
authors.initials: HR
authors.lastname: Waterham
authors.forename: F
authors.initials: F
authors.lastname: Baas
authors.forename: D J
authors.initials: DJ
authors.lastname: Richel
authors.forename: A H
authors.initials: AH
authors.lastname: van Gennip
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D042943:Dihydrouracil Dehydrogenase (NADP); D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity*; D005787:Gene Frequency; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D009154:Mutation; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012150:Polymorphism, Restriction Fragment Length; D013941:Thymine / Q000097:blood; D014498:Uracil / Q000097:blood
chemical_list: D000964:Antimetabolites, Antineoplastic; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013941:Thymine; D005472:Fluorouracil