title: Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.
abstract: 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.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively 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.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>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.1679T>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.
authors.affiliation: Department of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Froehlich
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.forename: Stefan
authors.initials: S
authors.lastname: Aebi
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-fluorouracil; DPYD; capecitabine; dihydropyrimidine dehydrogenase gene; drug safety; fluoropyrimidine; pharmacogenetics