title: Contribution of the β-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity.
abstract: BACKGROUND
  An impairment of the 5-fluorouracil (5-FU) catabolic pathway, represented by alterations in the dihydropyrimidine dehydrogenase (DPYD) gene, is considered a crucial factor contributing to the development of 5-FU-related toxicity. The β-ureidopropionase (BUP1) enzyme catalyzes the final step in the 5-FU catabolic pathway; however, alterations in the UPB1 gene coding for the BUP1 enzyme have not yet been analyzed in fluoropyrimidine (FP)-treated patients suffering from 5-FU-related toxicity.
  
  
  METHODS
  We have performed a mutation analysis of the entire coding sequence of UPB1 based on denaturing high-performance liquid chromatography in 113 cancer patients treated by FP-containing regimes. These patients included 67 individuals suffering from severe 5-FU-related toxicity and 46 individuals with excellent tolerance of chemotherapy.
  
  
  RESULTS
  Nine UPB1 variants were detected in the subpopulation of patients with severe toxicity, including a novel mutation affecting the coding sequence (c.872_873+11del13). An analysis of UPB1 variants on 5-FU-related toxicity in the population of all analyzed patients revealed an association between the c.-80C>G (rs2070474) variant and gastrointestinal toxicity. A strong positive correlation was found between the carriers of the c.-80 GG genotype and the development of severe (grade 3-4) mucositis (OR = 7.5; 95% CI = 2.60 - 21.60; p = 0.0002).
  
  
  CONCLUSIONS
  Our results suggest that UPB1 variants may contribute to the development of 5-FU-related toxicity in some FP-treated patients; however, the role of UPB1 alterations is probably less significant than that of DPYD alterations.
authors.affiliation: Institute of Biochemistry and Experimental Oncology, Charles University in Prague, First Faculty of Medicine, U Nemocnice 5, 128 53 Prague 2, Czech Republic.
authors.forename: Julie
authors.initials: J
authors.lastname: Fidlerova
authors.forename: Petra
authors.initials: P
authors.lastname: Kleiblova
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kormunda
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Kleibl
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C085968:UBP1 protein, human; D005472:Fluorouracil