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. 2016 Feb 25;11(2):e0148177.
doi: 10.1371/journal.pone.0148177. eCollection 2016.

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

Siew-Kee Low  1   2 , Koya Fukunaga  1 , Atsushi Takahashi  1 , Koichi Matsuda  3 , Fumiya Hongo  4 , Hiroyuki Nakanishi  4 , Hiroshi Kitamura  5 , Takamitsu Inoue  6 , Yoichiro Kato  7 , Yoshihiko Tomita  8 , Satoshi Fukasawa  9 , Tomoaki Tanaka  10 , Kazuo Nishimura  11 , Hirotsugu Uemura  12 , Isao Hara  13 , Masato Fujisawa  14 , Hideyasu Matsuyama  15 , Katsuyoshi Hashine  16 , Katsunori Tatsugami  17 , Hideki Enokida  18 , Michiaki Kubo  1 , Tsuneharu Miki  4 , Taisei Mushiroda  1
Affiliations

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

Siew-Kee Low et al. PLoS One. .

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 = 7.77x10(-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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Conflict of interest statement

Competing Interests: Professor Tsuneharu Miki has received funding from Pfizer, Inc. to carry out part of this study; however, this does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. ROC curve of the combined effects of ABCG2 421C>A (Q141K) and age with severe thrombocytopenia.
Fig 2
Fig 2. Histogram plot with case-control frequency versus distribution of log (OR).
Threshold of the plot was obtained from AUC curve with optimal sensitivity and specificity. Significant difference (P = 1.12x10-5) was observed between risk and non-risk of case-control in this study with odds ratio of 4.30 (95%CI = 2.07–9.10).
See this image and copyright information in PMC

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