title: 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.
abstract: 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.
authors.affiliation: Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokouchi
authors.affiliation: Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.affiliation: Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.|Clinical Oncology Center, Fukushima Medical University Hospital, Fukushima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.|Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Oizumi
authors.affiliation: Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan.|Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.affiliation: Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Akie
authors.affiliation: Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sugaya
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: First Department of Medicine, Obihiro Kosei Hospital, Obihiro, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takamura
authors.affiliation: Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan.|Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan.|Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Honjo
authors.affiliation: Respiratory Center, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Center for Integrated Science and Humanities, Fukushima Medical University, Fukushima, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Goto
authors.affiliation: Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
authors.affiliation: Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Isobe
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Munakata
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018287:Carcinoma, Large Cell / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D008297:Male; D056892:Mediator Complex / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C460107:MED12 protein, human; D056892:Mediator Complex; D018125:Receptors, Transforming Growth Factor beta; D019009:Proto-Oncogene Proteins c-kit; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: MED12; c-kit; immunohistochemistry; small-cell lung cancer; surgery