Dihydropyrimidinase and beta-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity

作者：Kummer Dominic; Froehlich Tanja K; Joerger Markus; Aebi Stefan; Sistonen Johanna; Amstutz Ursula; Largiader Carlo R^*

来源：Pharmacogenomics, 2015, 16(12): 1367-1377.

DOI：10.2217/PGS.15.81

• 5-fluorouracil
• beta-ureidopropionase
• capecitabine
• dihydropyrimidinase
• DPYS
• fluoropyrimidine
• gene variation
• pharmacogenomics
• toxicity
• UPB1

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.

• 出版日期2015