Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity

Hamzic, Seid; Kummer, Dominic; Milesi, S; Mueller, D; Joerger, M; Aebi, S; Amstutz, Ursula; Largiadèr, Carlo Rodolfo (2017). Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity. Clinical pharmacology & therapeutics, 102(5), pp. 796-804. Wiley 10.1002/cpt.641

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Hamzic, Seid; Kummer, Dominic; Amstutz, Ursula and Largiadèr, Carlo Rodolfo

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0009-9236

Publisher:

Wiley

Language:

English

Submitter:

Marie-Christine Müller

Date Deposited:

26 Mar 2018 16:43

Last Modified:

29 Oct 2019 16:19

Publisher DOI:

10.1002/cpt.641

BORIS DOI:

10.7892/boris.111437

URI:

https://boris.unibe.ch/id/eprint/111437

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