Immunohistochemical profiling of receptor tyrosine kinases, MED 12 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 & 5 others Hiroyuki Suzuki, Hirotoshi D. Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura, Mitsuru Munakata

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)39711-39726
Number of pages16
JournalOncotarget
Volume8
Issue number24
DOIs
Publication statusPublished - 2017 Jan 1
Externally publishedYes

Fingerprint

Small Cell Lung Carcinoma
Receptor Protein-Tyrosine Kinases
Mediator Complex
Survival
Immunohistochemistry
Proto-Oncogene Proteins c-kit
Vascular Endothelial Growth Factor Receptor-2
Adjuvant Chemotherapy
Epidermal Growth Factor Receptor
Paraffin
Formaldehyde
transforming growth factor-beta type II receptor
Neoplasms
Cytoplasm
Multivariate Analysis
Confidence Intervals
Recurrence

Keywords

  • C-kit
  • Immunohistochemistry
  • MED12
  • Small-cell lung cancer
  • Surgery

ASJC Scopus subject areas

  • Oncology

Cite this

Immunohistochemical profiling of receptor tyrosine kinases, MED 12 and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker. / Yokouchi, Hiroshi; Nishihara, Hiroshi; Harada, Toshiyuki; Ishida, Takashi; Yamazaki, Shigeo; Kikuchi, Hajime; Oizumi, Satoshi; Uramoto, Hidetaka; Tanaka, Fumihiro; Harada, Masao; Akie, Kenji; Sugaya, Fumiko; Fujita, Yuka; Takamura, Kei; Kojima, Tetsuya; Higuchi, Mitsunori; Honjo, Osamu; Minami, Yoshinori; Watanabe, Naomi; Goto, Aya; Suzuki, Hiroyuki; Dosaka-Akita, Hirotoshi D.; Isobe, Hiroshi; Nishimura, Masaharu; Munakata, Mitsuru.

In: Oncotarget, Vol. 8, No. 24, 01.01.2017, p. 39711-39726.

Research output: Contribution to journalArticle

Yokouchi, H, Nishihara, H, Harada, T, Ishida, T, Yamazaki, S, Kikuchi, H, Oizumi, S, Uramoto, H, Tanaka, F, Harada, M, Akie, K, Sugaya, F, Fujita, Y, Takamura, K, Kojima, T, Higuchi, M, Honjo, O, Minami, Y, Watanabe, N, Goto, A, Suzuki, H, Dosaka-Akita, HD, Isobe, H, Nishimura, M & Munakata, M 2017, 'Immunohistochemical profiling of receptor tyrosine kinases, MED 12 and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker', Oncotarget, vol. 8, no. 24, pp. 39711-39726. https://doi.org/10.18632/oncotarget.14410
Yokouchi, Hiroshi ; Nishihara, Hiroshi ; Harada, Toshiyuki ; Ishida, Takashi ; Yamazaki, Shigeo ; Kikuchi, Hajime ; Oizumi, Satoshi ; Uramoto, Hidetaka ; Tanaka, Fumihiro ; Harada, Masao ; Akie, Kenji ; Sugaya, Fumiko ; Fujita, Yuka ; Takamura, Kei ; Kojima, Tetsuya ; Higuchi, Mitsunori ; Honjo, Osamu ; Minami, Yoshinori ; Watanabe, Naomi ; Goto, Aya ; Suzuki, Hiroyuki ; Dosaka-Akita, Hirotoshi D. ; Isobe, Hiroshi ; Nishimura, Masaharu ; Munakata, Mitsuru. / Immunohistochemical profiling of receptor tyrosine kinases, MED 12 and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker. In: Oncotarget. 2017 ; Vol. 8, No. 24. pp. 39711-39726.
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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.",
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AU - Harada, Toshiyuki

AU - Ishida, Takashi

AU - Yamazaki, Shigeo

AU - Kikuchi, Hajime

AU - Oizumi, Satoshi

AU - Uramoto, Hidetaka

AU - Tanaka, Fumihiro

AU - Harada, Masao

AU - Akie, Kenji

AU - Sugaya, Fumiko

AU - Fujita, Yuka

AU - Takamura, Kei

AU - Kojima, Tetsuya

AU - Higuchi, Mitsunori

AU - Honjo, Osamu

AU - Minami, Yoshinori

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AU - Suzuki, Hiroyuki

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