title: Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity.
abstract: An important concern with the anticancer drug capecitabine (Cp), an oral prodrug of 5-fluorouracil, are dose-limiting adverse effects, in particular hand-foot syndrome (HFS) and diarrhea. Here we evaluated the association of genetic variability in all enzymes of the Cp-activation pathway to 5-fluorouracil with Cp-related early-onset toxicity in 144 patients receiving Cp. We identified a haplotype encompassing five variants in the carboxylesterase 1 (CES1) gene region including an expression quantitative trait locus associated with early-onset Cp-toxicity (Haplotype A3: ORadditive= 2.2, 95% CI 1.2-4.0, Padjusted= 0.012; ORrecessive= 10.3, 95% CI 2.1-49.4, Padjusted= 0.0038). Furthermore, the association of two linked cytidine deaminase (CDA) promoter variants (c.1-451C>T: ORdominant= 4.3, 95% CI 1.3-14.2, Padjusted= 0.017; and c.1-92A>G: ORdominant= 4.4, 95% CI 1.3-14.5, Padjusted= 0.015) with Cp-related diarrhea was replicated. This first study identifying an association of genetic variation in CES1 with Cp-related toxicity provides further evidence for the existence of a functional noncoding CES1-variant with a possible regulatory impact.
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Hamzic
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Kummer
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Milesi
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Mueller
authors.affiliation: Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Division of Medical Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Aebi
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Amstutz
authors.affiliation: Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: C R
authors.initials: CR
authors.lastname: Largiader
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000069287:Capecitabine / Q000009:adverse effects*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D015331:Cohort Studies; D005544:Forecasting; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D011355:Prodrugs / Q000009:adverse effects*; D012720:Severity of Illness Index
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D000069287:Capecitabine; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human