title: Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Restriction fragment length polymorphism (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.
authors.affiliation: Department of Clinical Genetics, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Ofverholm
authors.forename: Eva
authors.initials: E
authors.lastname: Arkblad
authors.forename: Stanko
authors.initials: S
authors.lastname: Skrtic
authors.forename: Per
authors.initials: P
authors.lastname: Albertsson
authors.forename: Emman
authors.initials: E
authors.lastname: Shubbar
authors.forename: Charlotta
authors.initials: C
authors.lastname: Enerbäck
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D012150:Polymorphism, Restriction Fragment Length; D017422:Sequence Analysis, DNA
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil