Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients

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 performed genotyping of DPYS based on denaturing high-performance liquid chromatography in 113 cancer patients including 67 with severe FP-related toxicity and 46 without toxicity excellently tolerating FPs treatment. 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. The CC carriers of the c.-1C alleles were at higher risk of mucositis (OR = 4.13; 95% CI = 1.51-11.31; P = 0.006) and gastrointestinal toxicity (OR = 3.54; 95% CI = 1.59-7.88; P = 0.002), whereas the presence of the IVS1-58C allele decreased the risk of gastrointestinal toxicity (OR = 0.4; 95% CI = 0.17-0.93; P = 0.03) and leucopenia (OR = 0.29; 95% CI = 0.08-1.01; P = 0.05). Our results indicate that missense and nonsense variants in DPYS are infrequent, however, the development of serious primarily gastrointestinal toxicity could be influenced by non-coding DPYS sequence variants c.-1T > C and IVS1-58T > C.