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Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
Isabela Martins Gonzaga1, Sheila Coelho Soares-Lima, Paulo Thiago Souza de Santos
1Programa 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.
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.
Insights
Targeted therapies for epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) may benefit only a small subset of esophageal squamous cell carcinoma (ESCC) patients due to infrequent mutations and overexpression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, necessitating novel treatment strategies.
- Epidermal growth factor receptors (EGFRs) are implicated in tumor development, making them targets for therapy.
Purpose of the Study:
- To investigate the expression of EGFR and HER2 in ESCC.
- To analyze EGFR, KRAS, and BRAF mutations in ESCC patients.
Main Methods:
- RT-qPCR and immunohistochemistry for EGFR and HER2 expression.
- Fluorescent in situ hybridization for gene amplification.
- Direct sequencing and PCR-RFLP for mutation analysis.
Main Results:
- EGFR mRNA was elevated in tumors (p <0.05), but protein overexpression was rare (4%).
- HER2 mRNA showed no median difference, but amplification occurred in 7% and protein overexpression in 21% (scores 2+/3+).
- No significant mutations in EGFR, KRAS, or BRAF hotspots were detected in nearly 100 patients; common EGFR polymorphisms were observed.
Conclusions:
- Targeted therapies for HER receptors are likely effective in a limited proportion of ESCC patients.
- The EGFR/HER2 signaling pathway is altered in a small fraction of ESCC cases.
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