title: Dihydropyrimidinase and β-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity.
abstract: OBJECTIVE
  To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy.
  
  
  METHODS
  The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients.
  
  
  CONCLUSIONS
  Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1-1T > C: p(adjusted) = 0.003; OR = 2.53; 95% CI: 1.39-4.62, and c.265-58T > C: p(adjusted) = 0.039; OR = 0.61; 95% CI: 0.38-0.97) with 5-fluorouracil toxicity were replicated.
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland.|Graduate School for Cellular & Biomedical Sciences, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Kummer
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Froehlich
authors.affiliation: Department of Medical Oncology & Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Division of Medical Oncology, Cantonal Hospital Lucerne, Spitalstrasse, CH-6000 Lucerne 16, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aebi
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Sistonen
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, & University of Bern, INO-F, CH-3010 Bern, Switzerland.
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000581:Amidohydrolases / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D016022:Case-Control Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; D000581:Amidohydrolases; C021590:beta-ureidopropionase; C020047:dihydropyrimidinase; D005472:Fluorouracil
keywords: 5-fluorouracil; DPYS; UPB1; capecitabine; dihydropyrimidinase; fluoropyrimidine; gene variation; pharmacogenomics; toxicity; β-ureidopropionase