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Open Access Research article

Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas

Isabela Martins Gonzaga1, Sheila Coelho Soares-Lima1, Paulo Thiago Souza de Santos1, Tania Cristina Moita Blanco2, Bruno Souza Bianchi de Reis3, Danielle Carvalho Quintella3, Ivanir Martins de Oliveira3, Paulo Antonio Silvestre de Faria3, Cleber Dario Pinto Kruel4, Nelson Adami Andreollo5, Tatiana Almeida de Simão12 and Luis Felipe Ribeiro Pinto12*

Author affiliations

1 Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Coordenação de Pesquisa, Rua André Cavalcanti, 37 – 6º andar, Bairro de Fátima, Rio de Janeiro, Rio de Janeiro, CEP: 20231-050, Brazil

2 Departamento de Bioquímica, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro 87 fundos, Vila Isabel, Rio de Janeiro, CEP: 20551-013, Brazil

3 Divisão de Patologia, Instituto Nacional de Câncer, Rua Cordeiro da Graça 156 Santo Cristo, Rio de Janeiro, Rio de Janeiro, CEP: 20.230-240, Brazil

4 Hospital de Clínicas de Porto Alegre, PPG-Ciências Cirúrgicas-Famed, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400 2o andar, Santana, Porto Alegre, Rio Grande do Sul, CEP: 90035-903, Brazil

5 Departamento de Cirurgia e Gastrocentro, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Rua Alexandre Fleming 181, Barão Geraldo, Campinas, São Paulo, CEP: 13081-970, Brazil

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Citation and License

BMC Cancer 2012, 12:569  doi:10.1186/1471-2407-12-569

Published: 4 December 2012

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) shows a 5-year survival rate below 10%, demonstrating the urgency in improving its treatment. Alterations in epidermal growth factor receptors are closely related to malignancy transformation in a number of tumors and recent successful targeted therapies have been directed to these molecules. Therefore, in this study, we analyzed the expression of EGFR and HER2 and evaluated EGFR mutation profile as well as the presence of mutations in hotspots of KRAS and BRAF in ESCC patients.

Methods

We performed RT-qPCR, immunohistochemistry and Fluorescent in situ hybridization to determine EGFR and HER2 expression in ESCC patients, and direct sequencing and PCR-RFLP for mutations and polymorphism analysis.

Results

Our results showed an increased EGFR mRNA expression in tumors compared to surrounding tissue (p <0.05), with 11% of the cases presenting at least a four-fold difference between tumor and paired adjacent mucosa. EGFR protein overexpression was present only in 4% of the cases. The median expression of HER2 mRNA was not different between tumors and adjacent mucosa. Still, 7% of the tumors presented at least a 25-fold higher expression of this gene when compared to its paired counterpart. Immunohistochemical analysis revealed that 21% of the tumors were positive for HER2 (scores 2+ and 3+), although only 3+ tumors presented amplification of this gene. Mutation analysis for EGFR (exons 18-21), KRAS (codons 12 and 13) and BRAF (V600E) showed no mutations in any of the hotspots of these genes in almost 100 patients analyzed. EGFR presented synonymous polymorphisms at codon 836 (C>T) in 2.1% of the patients, and at codon 787 (G>A) in 79.2% of the cases. This last polymorphism was also evaluated in 304 healthy controls, which presented a similar frequency (73.7%) in comparison with ESCC patients. The absence of mutations of EGFR, KRAS and BRAF as well as the overexpression of EGFR and HER2 in less than 10% of the patients suggest that this signaling pathway is altered in only a small proportion of patients with ESCC.

Conclusion

HER receptors target therapies may have the potential to be effective in only a minor fraction of patients with ESCC.

Keywords:
Esophageal cancer; EGFR; HER2; KRAS; BRAF; Target therapy