Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients.
Abstract
Decreased 5-fluorouracil catabolism has been considered a major factor contributing to fluoropyrimidine (FP)-related toxicity. Alterations in the dihydropyrimidine dehydrogenase gene coding for the first and rate-limiting enzyme of FP catabolic pathway could explain toxicity in only a limited proportion of FP-treated patients.
The importance of gene variants in dihydropyrimidinase (DPYS) coding for subsequent catabolic enzyme of FP degradation is not fully understood. We detected nine DPYS variants including four located in non-coding sequence (c.-1T>C, IVS1+34C>G, IVS1-58T>C, and novel IVS4+11G>T), four silent (c.15G>A, c.216C>T, and novel c.105C>T and c.324C>A), and one novel missense variant c.1441C>T (p.R481W).
All novel alterations were detected once only in patients without toxicity. The c.-1T>C and IVS1-58T>C variants were found to modify the risk of toxicity.