Clinical Research Papers:

Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker

Hiroshi Yokouchi _, Hiroshi Nishihara, Toshiyuki Harada, Takashi Ishida, Shigeo Yamazaki, Hajime Kikuchi, Satoshi Oizumi, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Aya Goto, Hiroyuki Suzuki, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura and Mitsuru Munakata

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Oncotarget. 2017; 8:39711-39726. https://doi.org/10.18632/oncotarget.14410

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Hiroshi Yokouchi1, Hiroshi Nishihara2, Toshiyuki Harada3, Takashi Ishida1,4, Shigeo Yamazaki5, Hajime Kikuchi6, Satoshi Oizumi6,7, Hidetaka Uramoto8,9, Fumihiro Tanaka8, Masao Harada7, Kenji Akie10, Fumiko Sugaya11, Yuka Fujita12, Kei Takamura13, Tetsuya Kojima14, Mitsunori Higuchi15,16, Osamu Honjo11,17, Yoshinori Minami18, Naomi Watanabe19, Aya Goto20, Hiroyuki Suzuki16, Hirotoshi Dosaka-Akita21, Hiroshi Isobe14, Masaharu Nishimura6 and Mitsuru Munakata1

1 Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan

2 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

3 Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan

4 Clinical Oncology Center, Fukushima Medical University Hospital, Fukushima, Japan

5 Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan

6 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan

7 Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan

8 Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan

9 Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan

10 Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan

11 Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan

12 Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan

13 First Department of Medicine, Obihiro Kosei Hospital, Obihiro, Japan

14 Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan

15 Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan

16 Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan

17 Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan

18 Respiratory Center, Asahikawa Medical University, Asahikawa, Japan

19 Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan

20 Center for Integrated Science and Humanities, Fukushima Medical University, Fukushima, Japan

21 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Correspondence to:

Hiroshi Yokouchi, email:

Keywords: small-cell lung cancer, surgery, MED12, c-kit, immunohistochemistry

Received: June 13, 2016 Accepted: December 01, 2016 Published: December 31, 2016


The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-βRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-βRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310–0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression (n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-βRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.

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