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

The Pharmacogenomics Journal volume 17, pages 319–324 (2017)Cite this article

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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; 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.

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Acknowledgements

We thank Gisela Andrey, Marion Ernst, Gabriela Mäder and Daniela Sommer for their laboratory work and Johanna Sistonen for helpful discussions. We also thank Simone Farese and all those involved from participating oncology centers for their contributions in patient recruitment and clinical data collection. We also thank the Swiss National Science Foundation for their financial support (Grants 119839 and 138285).

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Author notes

  1. S Hamzic and N Wenger: These two authors contributed equally to this work.

Authors and Affiliations

  1. University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    S Hamzic, N Wenger, T K Froehlich, C R Largiadèr & U Amstutz

  2. Department of Medical Oncology, Cantonal Hospital St Gallen, St Gallen, Switzerland

    M Joerger

  3. Division of Medical Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland

    S Aebi

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  1. S Hamzic
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Correspondence to U Amstutz.

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Hamzic, S., Wenger, N., Froehlich, T. et al. The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity. Pharmacogenomics J 17, 319–324 (2017). https://doi.org/10.1038/tpj.2016.23

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