Association study of a functional variant on ABCG2 gene with sunitinib-induced severe adverse drug reaction

Siew Kee Low, Koya Fukunaga, Atsushi Takahashi, Koichi Matsuda, Fumiya Hongo, Hiroyuki Nakanishi, Hiroshi Kitamura, Takamitsu Inoue, Yoichiro Kato, Yoshihiko Tomita, Satoshi Fukasawa, Tomoaki Tanaka, Kazuo Nishimura, Hirotsugu Uemura, Isao Hara, Masato Fujisawa, Hideyasu Matsuyama, Katsuyoshi Hashine, Katsunori Tatsugami, Hideki EnokidaMichiaki Kubo, Tsuneharu Miki, Taisei Mushiroda

Research output: Contribution to journalArticle

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Abstract

Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77×10-3, odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87×10-2, OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41×10-3, OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

Original languageEnglish
Article numbere0148177
JournalPloS one
Volume11
Issue number2
DOIs
Publication statusPublished - 01-02-2016

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thrombocytopenia
kidney cells
Drug-Related Side Effects and Adverse Reactions
carcinoma
Genes
drugs
odds ratio
Renal Cell Carcinoma
Pharmaceutical Preparations
Thrombocytopenia
genes
pharmacogenomics
drug toxicity
Odds Ratio
terminology
Toxicity
multivariate analysis
pharmacokinetics
tyrosine
germ cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Low, S. K., Fukunaga, K., Takahashi, A., Matsuda, K., Hongo, F., Nakanishi, H., ... Mushiroda, T. (2016). Association study of a functional variant on ABCG2 gene with sunitinib-induced severe adverse drug reaction. PloS one, 11(2), [e0148177]. https://doi.org/10.1371/journal.pone.0148177
Low, Siew Kee ; Fukunaga, Koya ; Takahashi, Atsushi ; Matsuda, Koichi ; Hongo, Fumiya ; Nakanishi, Hiroyuki ; Kitamura, Hiroshi ; Inoue, Takamitsu ; Kato, Yoichiro ; Tomita, Yoshihiko ; Fukasawa, Satoshi ; Tanaka, Tomoaki ; Nishimura, Kazuo ; Uemura, Hirotsugu ; Hara, Isao ; Fujisawa, Masato ; Matsuyama, Hideyasu ; Hashine, Katsuyoshi ; Tatsugami, Katsunori ; Enokida, Hideki ; Kubo, Michiaki ; Miki, Tsuneharu ; Mushiroda, Taisei. / Association study of a functional variant on ABCG2 gene with sunitinib-induced severe adverse drug reaction. In: PloS one. 2016 ; Vol. 11, No. 2.
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abstract = "Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43{\%} (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77×10-3, odds ratio (OR) = 1.04, 95{\%}CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87×10-2, OR = 1.71, 95{\%}CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41×10-3, OR = 1.86, 95{\%} CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.",
author = "Low, {Siew Kee} and Koya Fukunaga and Atsushi Takahashi and Koichi Matsuda and Fumiya Hongo and Hiroyuki Nakanishi and Hiroshi Kitamura and Takamitsu Inoue and Yoichiro Kato and Yoshihiko Tomita and Satoshi Fukasawa and Tomoaki Tanaka and Kazuo Nishimura and Hirotsugu Uemura and Isao Hara and Masato Fujisawa and Hideyasu Matsuyama and Katsuyoshi Hashine and Katsunori Tatsugami and Hideki Enokida and Michiaki Kubo and Tsuneharu Miki and Taisei Mushiroda",
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Low, SK, Fukunaga, K, Takahashi, A, Matsuda, K, Hongo, F, Nakanishi, H, Kitamura, H, Inoue, T, Kato, Y, Tomita, Y, Fukasawa, S, Tanaka, T, Nishimura, K, Uemura, H, Hara, I, Fujisawa, M, Matsuyama, H, Hashine, K, Tatsugami, K, Enokida, H, Kubo, M, Miki, T & Mushiroda, T 2016, 'Association study of a functional variant on ABCG2 gene with sunitinib-induced severe adverse drug reaction', PloS one, vol. 11, no. 2, e0148177. https://doi.org/10.1371/journal.pone.0148177

Association study of a functional variant on ABCG2 gene with sunitinib-induced severe adverse drug reaction. / Low, Siew Kee; Fukunaga, Koya; Takahashi, Atsushi; Matsuda, Koichi; Hongo, Fumiya; Nakanishi, Hiroyuki; Kitamura, Hiroshi; Inoue, Takamitsu; Kato, Yoichiro; Tomita, Yoshihiko; Fukasawa, Satoshi; Tanaka, Tomoaki; Nishimura, Kazuo; Uemura, Hirotsugu; Hara, Isao; Fujisawa, Masato; Matsuyama, Hideyasu; Hashine, Katsuyoshi; Tatsugami, Katsunori; Enokida, Hideki; Kubo, Michiaki; Miki, Tsuneharu; Mushiroda, Taisei.

In: PloS one, Vol. 11, No. 2, e0148177, 01.02.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association study of a functional variant on ABCG2 gene with sunitinib-induced severe adverse drug reaction

AU - Low, Siew Kee

AU - Fukunaga, Koya

AU - Takahashi, Atsushi

AU - Matsuda, Koichi

AU - Hongo, Fumiya

AU - Nakanishi, Hiroyuki

AU - Kitamura, Hiroshi

AU - Inoue, Takamitsu

AU - Kato, Yoichiro

AU - Tomita, Yoshihiko

AU - Fukasawa, Satoshi

AU - Tanaka, Tomoaki

AU - Nishimura, Kazuo

AU - Uemura, Hirotsugu

AU - Hara, Isao

AU - Fujisawa, Masato

AU - Matsuyama, Hideyasu

AU - Hashine, Katsuyoshi

AU - Tatsugami, Katsunori

AU - Enokida, Hideki

AU - Kubo, Michiaki

AU - Miki, Tsuneharu

AU - Mushiroda, Taisei

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77×10-3, odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87×10-2, OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41×10-3, OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

AB - Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77×10-3, odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87×10-2, OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41×10-3, OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

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