• Open Access

Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia

Authors

  • Kazuma Kiyotani,

    1. Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo 108-8639;
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  • Taisei Mushiroda,

    1. Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo 108-8639;
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  • Michiaki Kubo,

    1. Laboratory for genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama 230-0045;
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  • Hitoshi Zembutsu,

    1. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639;
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  • Yuichi Sugiyama,

    Corresponding author
    1. Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
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  • Yusuke Nakamura

    Corresponding author
    1. Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo 108-8639;
    2. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639;
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To whom all correspondence should be addressed. E-mail: yusuke@ims.u-tokyo.ac.jp

Abstract

Despite long-term clinical experience with docetaxel, unpredictable severe adverse reactions remain an important determinant for limiting the use of the drug. To identify a genetic factor(s) determining the risk of docetaxel-induced leukopenia/neutropenia, we selected subjects who received docetaxel chemotherapy from samples recruited at BioBank Japan, and conducted a case–control association study. We genotyped 84 patients, 28 patients with grade 3 or 4 leukopenia/neutropenia, and 56 with no toxicity (patients with grade 1 or 2 were excluded), for a total of 79 single nucleotide polymorphisms (SNPs) in seven genes possibly involved in the metabolism or transport of this drug: CYP3A4, CYP3A5, ABCB1, ABCC2, SLCO1B3, NR1I2, and NR1I3. Since one SNP in ABCB1, four SNPs in ABCC2, four SNPs in SLCO1B3, and one SNP in NR1I2 showed a possible association with the grade 3 leukopenia/neutropenia (P-value of <0.05), we further examined these 10 SNPs using 29 additionally obtained patients, 11 patients with grade 3/4 leukopenia/neutropenia, and 18 with no toxicity. The combined analysis indicated a significant association of rs12762549 in ABCC2 (P = 0.00022) and rs11045585 in SLCO1B3 (P = 0.00017) with docetaxel-induced leukopenia/neutropenia. When patients were classified into three groups by the scoring system based on the genotypes of these two SNPs, patients with a score of 1 or 2 were shown to have a significantly higher risk of docetaxel-induced leukopenia/neutropenia as compared to those with a score of 0 (P = 0.0000057; odds ratio [OR], 7.00; 95% CI [confidence interval], 2.95–16.59). This prediction system correctly classified 69.2% of severe leukopenia/neutropenia and 75.7% of non-leukopenia/neutropenia into the respective categories, indicating that SNPs in ABCC2 and SLCO1B3 may predict the risk of leukopenia/neutropenia induced by docetaxel chemotherapy. (Cancer Sci 2008; 99: 967–972)

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