Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity
S Hamzic, D Kummer, S Milesi, D Mueller, Markus Joerger, S Aebi, U Amstutz & C R Largiader
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abstract
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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.
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citation
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Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz
U, Largiader C R. Novel Genetic Variants in Carboxylesterase 1
Predict Severe Early-Onset Capecitabine-Related Toxicity. Clin
Pharmacol Ther 2017; 102:796-804.
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type
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journal paper/review (English)
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date of publishing
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30-05-2017
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journal title
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Clin Pharmacol Ther (102/5)
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ISSN electronic
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1532-6535
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pages
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796-804
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PubMed
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28139840
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DOI
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10.1002/cpt.641
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