Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

Kato,Hiroaki; Arao,Tokuzo; Matsumoto,Kazuko; Fujita,Yoshihiko; Kimura,Hideharu; Hayashi,Hidetoshi; Nishiki,Kouhei; Iwama,Mitsuru; Shiraishi,Osamu; Yasuda,Atsushi; Shinkai,Masayuki; Imano,Motohiro; Imamoto,Haruhiko; Yasuda,Takushi; Okuno,Kiyotaka; Shiozaki,Hitoshi; Nishio,Kazuto

doi:10.3892/ijo.2013.1830

April 2013 Volume 42 Issue 4

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April 2013 Volume 42 Issue 4

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Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

Authors:
- Hiroaki Kato
- Tokuzo Arao
- Kazuko Matsumoto
- Yoshihiko Fujita
- Hideharu Kimura
- Hidetoshi Hayashi
- Kouhei Nishiki
- Mitsuru Iwama
- Osamu Shiraishi
- Atsushi Yasuda
- Masayuki Shinkai
- Motohiro Imano
- Haruhiko Imamoto
- Takushi Yasuda
- Kiyotaka Okuno
- Hitoshi Shiozaki
- Kazuto Nishio
View Affiliations / Copyright

Affiliations: Department of Surgery, Kinki University Faculty of Medicine, Osaka 589-8511, Japan, Department of Genome Biology, Kinki University Faculty of Medicine, Osaka 589-8511, Japan

Copyright: © Kato et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Pages: 1151-1158
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Published online on: February 19, 2013

https://doi.org/10.3892/ijo.2013.1830
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Abstract

Molecular targeted therapy is expected to be a promising therapeutic approach for the treatment of esophageal squamous cell carcinoma (ESCC); however, the gene amplification status of molecular targeted genes in ESCC remains largely unclear. The gene amplification of EGFR, HER2, FGFR2 and MET was examined using a real-time PCR-based copy number assay of 245 ESCC surgical specimens of formalin-fixed, paraffin-embedded samples. Fluorescence in situ hybridization (FISH) and comparative genomic hybridization analyses verified the results of the copy number assay. EGFR mutation was detected using the Scorpions-ARMS method. The EGFR status and drug sensitivity to an EGFR tyrosine kinase inhibitor was then evaluated in vitro. Gene amplification of EGFR and HER2 was observed in 7% (16/244) and 11% (27/245) of the ESCC specimens. A multivariate analysis revealed that HER2 amplification was a significant predictor of a poor prognosis in patients with stage III post-operative ESCC. The L861Q type of EGFR mutation with hypersensitivity to EGFR tyrosine kinase inhibitor was found in one of the eight ESCC cell lines and one del745 type of EGFR mutation was identified in 107 clinical samples. In addition, we demonstrated for the first time that FGFR2 amplification was observed in 4% (8/196) of the ESCC specimens. MET amplification was observed in 1% (2/196). In conclusion, the frequent gene amplification of EGFR, HER2 and FGFR2 and the presence of active EGFR mutations were observed in ESCC specimens. Our results strongly encourage the development of molecular targeted therapy for ESCC.

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1	Ando N, Ozawa S, Kitagawa Y, Shinozawa Y and Kitajima M: Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg. 232:225–232. 2002.PubMed/NCBI
2	Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T and Hatakeyama K: Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg. 198:205–211. 2004. View Article : Google Scholar
3	Normanno N, De Luca A, Bianco C, et al: Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 366:2–16. 2006. View Article : Google Scholar : PubMed/NCBI
4	Shepard HM, Brdlik CM and Schreiber H: Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family. J Clin Invest. 118:3574–3581. 2008. View Article : Google Scholar : PubMed/NCBI
5	Hanawa M, Suzuki S, Dobashi Y, et al: EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer. 118:1173–1180. 2006. View Article : Google Scholar : PubMed/NCBI
6	Sunpaweravong P, Sunpaweravong S, Puttawibul P, et al: Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 131:111–119. 2005. View Article : Google Scholar : PubMed/NCBI
7	Zhan N, Dong WG, Tang YF, Wang ZS and Xiong CL: Analysis of HER2 gene amplification and protein expression in esophageal squamous cell carcinoma. Med Oncol. 29:933–940. 2011. View Article : Google Scholar : PubMed/NCBI
8	Sato-Kuwabara Y, Neves JI, Fregnani JHTG, Sallum RA and Soares FA: Evaluation of gene amplification and protein expression of HER-2/neu in esophageal squamous cell carcinoma using fluorescence in situ hybridization (FISH) and immunohistochemistry. BMC Cancer. 9:1207–1471. 2009. View Article : Google Scholar : PubMed/NCBI
9	Mimura K, Kono K, Hanawa M, et al: Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma. Br J Cancer. 92:1253–1260. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
11	Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
12	Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemo-therapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
13	Peták I, Schwab R, Orfi L, Kopper L and Kéri G: Integrating molecular diagnostics into anticancer drug discovery. Nat Rev Drug Discov. 9:523–535. 2010.PubMed/NCBI
14	Turner N and Grose R: Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 10:116–129. 2010. View Article : Google Scholar : PubMed/NCBI
15	Matsumoto K, Arao T, Hamaguchi T, et al: FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer. 106:727–732. 2012. View Article : Google Scholar : PubMed/NCBI
16	Takeda M, Arao T, Yokote H, et al: AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res. 13:3051–3057. 2007. View Article : Google Scholar
17	Gherardi E, Birchmeier W, Birchmeier C and Vande Woude G: Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 12:89–103. 2012. View Article : Google Scholar : PubMed/NCBI
18	Cappuzzo F, Marchetti A, Skokan M, et al: Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 27:1667–1674. 2009. View Article : Google Scholar : PubMed/NCBI
19	Kimura H, Kasahara K, Kawaishi M, et al: Detection of epidermal growth factor receptor mutations in serum as a predictor of the response to gefitinib in patients with non-small-cell lung cancer. Clin Cancer Res. 12:3915–3921. 2006. View Article : Google Scholar : PubMed/NCBI
20	Kaneda H, Arao T, Tanaka K, et al: FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res. 70:2053–2063. 2010. View Article : Google Scholar : PubMed/NCBI
21	Matsumoto K, Arao T, Tanaka K, et al: mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells. Cancer Res. 69:7160–7164. 2009. View Article : Google Scholar : PubMed/NCBI
22	Kunii K, Davis L, Gorenstein J, et al: FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res. 68:2340–2348. 2008. View Article : Google Scholar : PubMed/NCBI
23	Dutt A, Salvesen HB, Chen TH, et al: Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc Natl Acad Sci USA. 105:8713–8717. 2008. View Article : Google Scholar : PubMed/NCBI
24	Lennerz JK, Kwak EL, Ackerman A, et al: MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 29:4803–4810. 2011. View Article : Google Scholar : PubMed/NCBI
25	Okines A, Cunningham D and Chau I: Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol. 8:492–503. 2011. View Article : Google Scholar : PubMed/NCBI
26	Kancha RK, Peschel C and Duyster J: The epidermal growth factor receptor-L861Q mutation increases kinase activity without leading to enhanced sensitivity toward epidermal growth factor receptor kinase inhibitors. J Thorac Oncol. 6:387–392. 2011. View Article : Google Scholar
27	Bang YJ, Van Cutsem E, Feyereislova A, et al: ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 376:687–697. 2010. View Article : Google Scholar
28	Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 354:567–578. 2006. View Article : Google Scholar : PubMed/NCBI
29	Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 359:1116–1127. 2008. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

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