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Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction

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 f...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767438/
https://www.ncbi.nlm.nih.gov/pubmed/26914831
http://dx.doi.org/10.1371/journal.pone.0148177
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author 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
author_facet 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
author_sort Low, Siew-Kee
collection PubMed
description 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 = 7.77x10(-3), odds ratio (OR) = 1.04, 95%CI = 1.01–1.07) and ABCG2 421C>A (P = 1.87x10(-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 = 8.41x10(-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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spelling pubmed-47674382016-03-09 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 PLoS One Research Article 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 = 7.77x10(-3), odds ratio (OR) = 1.04, 95%CI = 1.01–1.07) and ABCG2 421C>A (P = 1.87x10(-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 = 8.41x10(-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. Public Library of Science 2016-02-25 /pmc/articles/PMC4767438/ /pubmed/26914831 http://dx.doi.org/10.1371/journal.pone.0148177 Text en © 2016 Low et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
title Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction
title_full Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction
title_fullStr Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction
title_full_unstemmed Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction
title_short Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction
title_sort association study of a functional variant on abcg2 gene with sunitinib-induced severe adverse drug reaction
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767438/
https://www.ncbi.nlm.nih.gov/pubmed/26914831
http://dx.doi.org/10.1371/journal.pone.0148177
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