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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 and Hideo Baba _

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Oncotarget. 2016; 7:19748-19761. https://doi.org/10.18632/oncotarget.7782

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Abstract

Ryuma Tokunaga1,*, Yu Imamura1,2,*, Kenichi Nakamura1, Takatsugu Ishimoto1, Shigeki Nakagawa1, Keisuke Miyake1, Yu Nakaji2,3, Yasuo Tsuda2, Masaaki Iwatsuki1, Yoshifumi Baba1, Yasuo Sakamoto1, Yuji Miyamoto1, Hiroshi Saeki2, Naoya Yoshida1, Eiji Oki2, Masayuki Watanabe1,2, Yoshinao Oda3, Adam J. Bass4,5,6, Yoshihiko Maehara2, Hideo Baba1

1Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

2Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

3Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

5Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

6Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

*These authors contributed equally to this work

Correspondence to:

Hideo Baba, e-mail: [email protected]

Keywords: esophagogastric junction adenocarcinoma, esophageal adenocarcinoma, FGFR2, targeting therapy, amplification

Received: November 02, 2015     Accepted: January 31, 2016     Published: February 27, 2016

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.

Conclusions: 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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