title: Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction.
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.
authors.affiliation: Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.|Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Siew-Kee
authors.initials: SK
authors.lastname: Low
authors.affiliation: Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Koya
authors.initials: K
authors.lastname: Fukunaga
authors.affiliation: Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Hongo
authors.affiliation: Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Sapporo Medical University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Akita University School of Medicine, Akita, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Iwate Medical University, Morioka, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Chiba Cancer Center, Chiba, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukasawa
authors.affiliation: Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
authors.affiliation: Wakayama Medical University, Wakayama, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Hara
authors.affiliation: Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujisawa
authors.affiliation: Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Matsuyama
authors.affiliation: Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Hashine
authors.affiliation: Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.affiliation: Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.affiliation: Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
authors.affiliation: Core for Genomic Medicine, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D044466:Asian People / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics; D007564:Japan; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000009:adverse effects* / Q000493:pharmacokinetics; D000077210:Sunitinib; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; D000077210:Sunitinib