title: Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia.
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.
authors.affiliation: Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo 108-8639, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D000090702:Constitutive Androstane Receptor; D000077143:Docetaxel; D005838:Genotype; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced*; D026901:Membrane Transport Proteins / Q000235:genetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009503:Neutropenia / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D011110:Polymorphism, Genetic; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D000090702:Constitutive Androstane Receptor; D000077143:Docetaxel; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D043823:Taxoids; C000715087:ABCC2 protein, human; C000716327:NR1I3 protein, human; C421209:SLCO1B3 protein, human