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

Detalhes bibliográficos
Autor(a) principal: Gonzaga, Isabela Martins
Data de Publicação: 2012
Outros Autores: Lima, Sheila Coelho Soares, Santos, Paulo Thiago de Souza, Blanco, Tania Cristina Moita, Reis, Bruno de Souza Bianchi, Quintella, Danielle Carvalho, Oliveira, Ivanir Martins de, Faria, Paulo Antonio Silvestre de, Kruel, Cleber Dario Pinto, Andreollo, Nelson Adami, Simão, Tatiana de Almeida, Pinto, Luis Felipe Ribeiro
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UFRGS
Texto Completo: http://hdl.handle.net/10183/111812
Resumo: 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.
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spelling Gonzaga, Isabela MartinsLima, Sheila Coelho SoaresSantos, Paulo Thiago de SouzaBlanco, Tania Cristina MoitaReis, Bruno de Souza BianchiQuintella, Danielle CarvalhoOliveira, Ivanir Martins deFaria, Paulo Antonio Silvestre deKruel, Cleber Dario PintoAndreollo, Nelson AdamiSimão, Tatiana de AlmeidaPinto, Luis Felipe Ribeiro2015-03-07T01:56:59Z20121471-2407http://hdl.handle.net/10183/111812000952985Background: 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.application/pdfengBMC cancer. London. Vol. 2012 (Dec. 2012), 10p.Neoplasias esofágicasGenes erbB-1Receptor erbB-2Terapia de alvo molecularEsophageal cancerEGFRHER2KRASBRAFTarget therapyAlterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomasEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSORIGINAL000952985.pdf000952985.pdfTexto completo (inglês)application/pdf2265411http://www.lume.ufrgs.br/bitstream/10183/111812/1/000952985.pdfbc3f9cab1167275f10bb83b7191735ddMD51TEXT000952985.pdf.txt000952985.pdf.txtExtracted Texttext/plain46666http://www.lume.ufrgs.br/bitstream/10183/111812/2/000952985.pdf.txt86d55099654699cf6b9b5fee2694989aMD52THUMBNAIL000952985.pdf.jpg000952985.pdf.jpgGenerated Thumbnailimage/jpeg1705http://www.lume.ufrgs.br/bitstream/10183/111812/3/000952985.pdf.jpgceb8ed6f410fdad2fe8e4d354489f1daMD5310183/1118122018-10-24 08:52:09.127oai:www.lume.ufrgs.br:10183/111812Repositório InstitucionalPUBhttps://lume.ufrgs.br/oai/requestlume@ufrgs.bropendoar:2018-10-24T11:52:09Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false
dc.title.pt_BR.fl_str_mv Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
title Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
spellingShingle Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
Gonzaga, Isabela Martins
Neoplasias esofágicas
Genes erbB-1
Receptor erbB-2
Terapia de alvo molecular
Esophageal cancer
EGFR
HER2
KRAS
BRAF
Target therapy
title_short Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
title_full Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
title_fullStr Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
title_full_unstemmed Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
title_sort Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas
author Gonzaga, Isabela Martins
author_facet Gonzaga, Isabela Martins
Lima, Sheila Coelho Soares
Santos, Paulo Thiago de Souza
Blanco, Tania Cristina Moita
Reis, Bruno de Souza Bianchi
Quintella, Danielle Carvalho
Oliveira, Ivanir Martins de
Faria, Paulo Antonio Silvestre de
Kruel, Cleber Dario Pinto
Andreollo, Nelson Adami
Simão, Tatiana de Almeida
Pinto, Luis Felipe Ribeiro
author_role author
author2 Lima, Sheila Coelho Soares
Santos, Paulo Thiago de Souza
Blanco, Tania Cristina Moita
Reis, Bruno de Souza Bianchi
Quintella, Danielle Carvalho
Oliveira, Ivanir Martins de
Faria, Paulo Antonio Silvestre de
Kruel, Cleber Dario Pinto
Andreollo, Nelson Adami
Simão, Tatiana de Almeida
Pinto, Luis Felipe Ribeiro
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Gonzaga, Isabela Martins
Lima, Sheila Coelho Soares
Santos, Paulo Thiago de Souza
Blanco, Tania Cristina Moita
Reis, Bruno de Souza Bianchi
Quintella, Danielle Carvalho
Oliveira, Ivanir Martins de
Faria, Paulo Antonio Silvestre de
Kruel, Cleber Dario Pinto
Andreollo, Nelson Adami
Simão, Tatiana de Almeida
Pinto, Luis Felipe Ribeiro
dc.subject.por.fl_str_mv Neoplasias esofágicas
Genes erbB-1
Receptor erbB-2
Terapia de alvo molecular
topic Neoplasias esofágicas
Genes erbB-1
Receptor erbB-2
Terapia de alvo molecular
Esophageal cancer
EGFR
HER2
KRAS
BRAF
Target therapy
dc.subject.eng.fl_str_mv Esophageal cancer
EGFR
HER2
KRAS
BRAF
Target therapy
description 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.
publishDate 2012
dc.date.issued.fl_str_mv 2012
dc.date.accessioned.fl_str_mv 2015-03-07T01:56:59Z
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dc.relation.ispartof.pt_BR.fl_str_mv BMC cancer. London. Vol. 2012 (Dec. 2012), 10p.
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