Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity

摘要

We Investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation C.1129-5923O6. Selected regions of DPYD were sequenced in prospectiveSy collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.H29-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.ll29-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% Ci = 2.30-6.09, p- 2 x 10"5) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.ll29-5923C>G/hapB3s c.1679T>G, c.1905 + 1G>A or c.2846A>T), 11 (all with c.ll29-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p= 5 x 10~6), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.H29-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.!679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.