Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma

Ryuma Tokunaga, Yu Imamura, Kenichi Nakamura, Takatsugu Ishimoto, Shigeki Nakagawa, Keisuke Miyake, Yu Nakaji, Yasuo Tsuda, Masaaki Iwatsuki, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Hiroshi Saeki, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Yoshinao Oda, Adam J. Bass, Yoshihiko Maehara, Hideo Baba

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. Patients and methods: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Results: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. Conclusion: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.

Original languageEnglish
Pages (from-to)19748-19761
Number of pages14
JournalOncotarget
Volume7
Issue number15
DOIs
Publication statusPublished - Apr 12 2016

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Receptor, Fibroblast Growth Factor, Type 2
Esophagogastric Junction
Adenocarcinoma
Survival
Growth
Neoplasms
Cell Proliferation
Cell Cycle

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. / Tokunaga, Ryuma; Imamura, Yu; Nakamura, Kenichi; Ishimoto, Takatsugu; Nakagawa, Shigeki; Miyake, Keisuke; Nakaji, Yu; Tsuda, Yasuo; Iwatsuki, Masaaki; Baba, Yoshifumi; Sakamoto, Yasuo; Miyamoto, Yuji; Saeki, Hiroshi; Yoshida, Naoya; Oki, Eiji; Watanabe, Masayuki; Oda, Yoshinao; Bass, Adam J.; Maehara, Yoshihiko; Baba, Hideo.

In: Oncotarget, Vol. 7, No. 15, 12.04.2016, p. 19748-19761.

Research output: Contribution to journalArticle

Tokunaga, R, Imamura, Y, Nakamura, K, Ishimoto, T, Nakagawa, S, Miyake, K, Nakaji, Y, Tsuda, Y, Iwatsuki, M, Baba, Y, Sakamoto, Y, Miyamoto, Y, Saeki, H, Yoshida, N, Oki, E, Watanabe, M, Oda, Y, Bass, AJ, Maehara, Y & Baba, H 2016, 'Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma', Oncotarget, vol. 7, no. 15, pp. 19748-19761. https://doi.org/10.18632/oncotarget.7782
Tokunaga, Ryuma ; Imamura, Yu ; Nakamura, Kenichi ; Ishimoto, Takatsugu ; Nakagawa, Shigeki ; Miyake, Keisuke ; Nakaji, Yu ; Tsuda, Yasuo ; Iwatsuki, Masaaki ; Baba, Yoshifumi ; Sakamoto, Yasuo ; Miyamoto, Yuji ; Saeki, Hiroshi ; Yoshida, Naoya ; Oki, Eiji ; Watanabe, Masayuki ; Oda, Yoshinao ; Bass, Adam J. ; Maehara, Yoshihiko ; Baba, Hideo. / Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 15. pp. 19748-19761.
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abstract = "Background: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. Patients and methods: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Results: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15{\%} and 61{\%}, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. Conclusion: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.",
author = "Ryuma Tokunaga and Yu Imamura and Kenichi Nakamura and Takatsugu Ishimoto and Shigeki Nakagawa and Keisuke Miyake and Yu Nakaji and Yasuo Tsuda and Masaaki Iwatsuki and Yoshifumi Baba and Yasuo Sakamoto and Yuji Miyamoto and Hiroshi Saeki and Naoya Yoshida and Eiji Oki and Masayuki Watanabe and Yoshinao Oda and Bass, {Adam J.} and Yoshihiko Maehara and Hideo Baba",
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T1 - Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma

AU - Tokunaga, Ryuma

AU - Imamura, Yu

AU - Nakamura, Kenichi

AU - Ishimoto, Takatsugu

AU - Nakagawa, Shigeki

AU - Miyake, Keisuke

AU - Nakaji, Yu

AU - Tsuda, Yasuo

AU - Iwatsuki, Masaaki

AU - Baba, Yoshifumi

AU - Sakamoto, Yasuo

AU - Miyamoto, Yuji

AU - Saeki, Hiroshi

AU - Yoshida, Naoya

AU - Oki, Eiji

AU - Watanabe, Masayuki

AU - Oda, Yoshinao

AU - Bass, Adam J.

AU - Maehara, Yoshihiko

AU - Baba, Hideo

PY - 2016/4/12

Y1 - 2016/4/12

N2 - Background: Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. Patients and methods: A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Results: Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. Conclusion: FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.

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