The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity
| Autor: | N Wenger, Carlo R. Largiadèr, Tanja K. Froehlich, Stefan Aebi, Ursula Amstutz, Markus Joerger, Seid Hamzic |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Risk 0301 basic medicine Antimetabolites Antineoplastic medicine.medical_specialty Adolescent Pharmacology Polymorphism Single Nucleotide Gastroenterology Young Adult 03 medical and health sciences 0302 clinical medicine Internal medicine Leukocytes Genetics medicine Dihydropyrimidine dehydrogenase Humans ABCC11 Aged Aged 80 and over Leukopenia biology Cancer Odds ratio Middle Aged medicine.disease Pyrimidines 030104 developmental biology Fluorouracil 030220 oncology & carcinogenesis Toxicity biology.protein Molecular Medicine ATP-Binding Cassette Transporters Female DPYD medicine.symptom medicine.drug |
| Zdroj: | The Pharmacogenomics Journal. 17:319-324 |
| ISSN: | 1473-1150 1470-269X |
| DOI: | 10.1038/tpj.2016.23 |
| Popis: | 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; Pc.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. |
| Databáze: | OpenAIRE |
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