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STAT3 Polymorphism Predicts Interferon-Alfa Response in Patients With Metastatic Renal Cell Carcinoma

Noriyuki Ito, Masatoshi Eto, Eijiro Nakamura, Atsushi Takahashi, Taiji Tsukamoto, Hiroshi Toma, Hayakazu Nakazawa, Yoshihiko Hirao, Hirotsugu Uemura, Susumu Kagawa, Hiroomi Kanayama, Yoshiaki Nose, Naoko Kinukawa, Tsuyoshi Nakamura, Nobuyoshi Jinnai, Toyokazu Seki, Masanobu Takamatsu, Yoshihiro Masui, Seiji Naito, Osamu Ogawa

From the Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto Department of Urology, Graduate School of Medical Sciences, Kyushu University; Department of Medical Informatics, Graduate School of Medical Sciences, Kyushu University, Fukuoka; Department of Urologic Surgery and Andrology, Sapporo Medical University School of Medicine, Hokkaido; Department of Urology, Tokyo Women's Medical University; Tokyo Women's Medical University Medical Center East; Therapeutic Application Development Department, Gastroenterology/Oncology Group, Otsuka Pharmaceutical Co Ltd, Tokyo; Department of Urology, Nara Medical University, Nara; Department of Urology, Kinki University School of Medicine, Osaka; National University Corporation Tokushima University Hospita; Department of Urology, Faculty of Medicine, the Tokushima University; Theranostics Research Center, Otsuka Pharmaceutical Co Ltd, Tokushima; and the Faculty of Environment Studies, Nagasaki University, Nagasaki, Japan

Address reprint requests to Osamu Ogawa, MD, Department of Urology, Graduate School of Medicine, Kyoto University, 54, Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; e-mail: ogawao{at}kuhp.kyoto-u.ac.jp

Purpose To clarify the effect of genetic polymorphisms on the response to interferon alfa (IFN-) for metastatic renal cell carcinoma (MRCC), and to find a reliable molecular marker to select those patients with MRCC who would benefit from IFN- immunotherapy.

Patients and Methods We carried out an association study in which 463 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in 75 Japanese patients who had received IFN- for MRCC.

Results After adjusting for lung metastasis, stepwise logistic regression analysis revealed that the SNPs in signal transducer and activator 3 (STAT3) were most significantly associated with better response to IFN-. Linkage disequilibrium mapping revealed that the SNP in the 5' region of STAT3, rs4796793, was the most significant predictor of IFN- response (odds ratio [OR] = 2.73; 95% CI, 1.38 to 5.78). The highest OR was shown in the CC genotype at rs4796793 compared to the GG + GC genotypes (OR = 8.38, 95% CI, 1.63 to 42.96). Genotype-dependent expressions of STAT3 in B lymphocyte cell lines and the enhanced growth inhibitory effects of IFN- by STAT3 suppression in an RCC cell line supported the results of the present association study.

Conclusion The present study suggested that the STAT3 polymorphism is a useful diagnostic marker to predict the response to IFN- therapy in patients with MRCC. An efficient response marker for IFN- needs to be utilized to establish individual optimal treatment strategies, even when newer drug therapies are used as first line treatments for MRCC.

Supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan Grant No. 18209049, 18014013, and a research grant from Japan Immunotherapy SNPs-Study Group for Kidney Cancer.

N.I. and M.E. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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