Aims: 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.
Patients & 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.
Results & 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.
Keywords: 5-fluorouracil; DPYS; UPB1; capecitabine; dihydropyrimidinase; fluoropyrimidine; gene variation; pharmacogenomics; toxicity; β-ureidopropionase.