title: Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-Fluorouracil toxicity in Portuguese colorectal cancer patients.
abstract: OBJECTIVE
  Dihydropyrimidine dehydrogenase is a critical enzyme in the catabolism of 5-Fluorouracil, a drug frequently used in cancer therapy. Patients with deficient dihydropyrimidine dehydrogenase activity are at risk of developing severe 5-Fluorouracil-associated toxicity. Genetic analysis of the gene coding for dihydropyrimidine dehydrogenase has shown that mutations in exon 14, especially the splice-site mutation IVS14+1G-->A, were associated with dihydropyrimidine dehydrogenase enzymatic deficiency.
  
  
  METHODS
  We evaluated the frequency of mutations in exon 14 of dihydropyrimidine dehydrogenase (DPYD) gene in 73 unselected colorectal cancer patients treated with 5-Fluorouracil after surgery at a Portuguese Cancer Institute.
  
  
  RESULTS
  Sequencing the entire exon 14 allowed the detection of mutations in two of the 73 patients (2.7%), namely two of the eight (25%) patients who presented grade 3-4 toxicity after 5-Fluorouracil chemotherapy. One patient was heterozygous for the splice-site mutation IVS14+1G-->A, whereas the second patient was heterozygous for a novel missense mutation 1845G-->T (E615D) in exon 14 of DPYD gene.
  
  
  CONCLUSIONS
  We conclude that mutations in exon 14 of DPYD gene are responsible for a significant proportion of life-threatening toxicity to 5-Fluorouracil, and should therefore be excluded before its administration to cancer patients.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Natália
authors.initials: N
authors.lastname: Salgueiro
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.forename: Maria
authors.initials: M
authors.lastname: Fragoso
authors.forename: Olga
authors.initials: O
authors.lastname: Sousa
authors.forename: Nuno
authors.initials: N
authors.lastname: Costa
authors.forename: Maria L
authors.initials: ML
authors.lastname: Pellon
authors.forename: Evaristo
authors.initials: E
authors.lastname: Sanches
authors.forename: José Guimarães
authors.initials: JG
authors.lastname: dos Santos
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Sérgio
authors.initials: S
authors.lastname: Castedo
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011174:Portugal; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA
chemical_list: D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil