1. The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity.
- Author
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Hamzic S, Wenger N, Froehlich TK, Joerger M, Aebi S, Largiadèr CR, and Amstutz U
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic adverse effects, Antimetabolites, Antineoplastic therapeutic use, Female, Fluorouracil adverse effects, Fluorouracil therapeutic use, Humans, Leukocytes drug effects, Male, Middle Aged, Pyrimidines therapeutic use, Risk, Young Adult, ATP-Binding Cassette Transporters genetics, Leukopenia chemically induced, Leukopenia genetics, Polymorphism, Single Nucleotide genetics, Pyrimidines adverse effects
- Abstract
A missense variant (c.1637C>T, T546M) in ABCC11 encoding the MRP8 (multidrug resistance protein 8), a transporter of 5-fluorodeoxyuridine monophosphate, has been associated with an increased risk of 5-fluorouracil-related severe leukopenia. To validate this association, we investigated the impact of the ABCC11 variants c.1637C>T, c.538G>A and c.395+1087C>T on the risk of early-onset fluoropyrimidine-related toxicity in 514 cancer patients. The ABCC11 variant c.1637C>T was strongly associated with severe leukopenia in patients carrying risk variants in DPYD, encoding the key fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase (odds ratio (OR): 71.0; 95% confidence interval (CI): 2.5-2004.8; P
c.1637C>T*DPYD =0.013). In contrast, in patients without DPYD risk variants, no association with leukopenia (OR: 0.95; 95% CI: 0.34-2.6) or overall fluoropyrimidine-related toxicity (OR: 1.02; 95% CI: 0.5-2.1) was observed. Our study thus suggests that c.1637C>T affects fluoropyrimidine toxicity to leukocytes particularly in patients with high drug exposure, for example, because of reduced fluoropyrimidine catabolism.- Published
- 2017
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