Publication

The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity

Journal Paper/Review - Mar 22, 2016

Units
PubMed
Doi

Citation
Hamzic S, Wenger N, Froehlich T, Jörger M, Aebi S, Largiader C, Amstutz U. The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity. Pharmacogenomics J 2016
Type
Journal Paper/Review (English)
Journal
Pharmacogenomics J 2016
Publication Date
Mar 22, 2016
Issn Electronic
1473-1150
Brief description/objective

UNASSIGNED
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.The Pharmacogenomics Journal advance online publication, 22 March 2016; doi:10.1038/tpj.2016.23.