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

Kazuma Kiyotani, Taisei Mushiroda, Michiaki Kubo, Hitoshi Zembutsu, Yuichi Sugiyama, Yusuke Nakamura

研究成果: Article

105 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)967-972
ページ数6
ジャーナルCancer Science
99
発行部数5
DOI
出版物ステータスPublished - 01-05-2008

Fingerprint

docetaxel
Leukopenia
Genetic Polymorphisms
Neutropenia
Single Nucleotide Polymorphism
Cytochrome P-450 CYP3A
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Kiyotani, Kazuma ; Mushiroda, Taisei ; Kubo, Michiaki ; Zembutsu, Hitoshi ; Sugiyama, Yuichi ; Nakamura, Yusuke. / Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. :: Cancer Science. 2008 ; 巻 99, 番号 5. pp. 967-972.
@article{869a9cd12aae40428f8f26c7ea60eee7,
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.",
author = "Kazuma Kiyotani and Taisei Mushiroda and Michiaki Kubo and Hitoshi Zembutsu and Yuichi Sugiyama and Yusuke Nakamura",
year = "2008",
month = "5",
day = "1",
doi = "10.1111/j.1349-7006.2008.00765.x",
language = "English",
volume = "99",
pages = "967--972",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "5",

}

Kiyotani, K, Mushiroda, T, Kubo, M, Zembutsu, H, Sugiyama, Y & Nakamura, Y 2008, 'Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia', Cancer Science, 巻. 99, 番号 5, pp. 967-972. https://doi.org/10.1111/j.1349-7006.2008.00765.x

Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia. / Kiyotani, Kazuma; Mushiroda, Taisei; Kubo, Michiaki; Zembutsu, Hitoshi; Sugiyama, Yuichi; Nakamura, Yusuke.

:: Cancer Science, 巻 99, 番号 5, 01.05.2008, p. 967-972.

研究成果: Article

TY - JOUR

T1 - Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia

AU - Kiyotani, Kazuma

AU - Mushiroda, Taisei

AU - Kubo, Michiaki

AU - Zembutsu, Hitoshi

AU - Sugiyama, Yuichi

AU - Nakamura, Yusuke

PY - 2008/5/1

Y1 - 2008/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=43649103816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43649103816&partnerID=8YFLogxK

U2 - 10.1111/j.1349-7006.2008.00765.x

DO - 10.1111/j.1349-7006.2008.00765.x

M3 - Article

C2 - 18294295

AN - SCOPUS:43649103816

VL - 99

SP - 967

EP - 972

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 5

ER -