Artigo Original
Carcinoma epidermóide do pulmão: Polissomia e amplificação do cromossoma 7 e do gene EGRF com forma wild type nos exões 19 e 21
Polysomy and amplification of chromosome 7 defined for EGFR gene in squamous cell carcinoma of the lung together with exons 19 and 21 wild type
Patrícia Couceiro1,3, Vítor Sousa1,2,3,4, Ana Alarcão1,3, Maria Silva1,3,4, Lina Carvalho1,2,3,4,
Corresponding author
lcarvalho@huc.min-saude.pt
Correspondence to: Prof. Dra. Lina Carvalho, MD, PhD., Instituto de Anatomia Patológica Faculdade de Medicina; Universidade de Coimbra 3000-054 Coimbra, Portugal. Tel. number: 00351239857762/65 Fax number: 00351239857704.
Correspondence to: Prof. Dra. Lina Carvalho, MD, PhD., Instituto de Anatomia Patológica Faculdade de Medicina; Universidade de Coimbra 3000-054 Coimbra, Portugal. Tel. number: 00351239857762/65 Fax number: 00351239857704.
1 Instituto de Patologia, Faculdade de Medicina, Universidade do Porto, Portugal/Institute of Pathology, Faculty of Medicine, University of Coimbra, Portugal
2 Serviço de Patologia, Hospitais da Universidade de Coimbra, Portugal/Pathology Service, Coimbra University Hospitals, Portugal
3 CIMAGO, Portugal
4 Serviço de Pneumologia, Hospitais da Universidade de Coimbra, Portugal/Pneumology Center, Coimbra University Hospitals, Portugal
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array:4 [ 0 => array:3 [ "entidad" => "Instituto de Patologia, Faculdade de Medicina, Universidade do Porto, Portugal/Institute of Pathology, Faculty of Medicine, University of Coimbra, Portugal" "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Serviço de Patologia, Hospitais da Universidade de Coimbra, Portugal/Pathology Service, Coimbra University Hospitals, Portugal" "etiqueta" => "<span class="elsevierStyleSup">2</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "CIMAGO, Portugal" "etiqueta" => "<span class="elsevierStyleSup">3</span>" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Serviço de Pneumologia, Hospitais da Universidade de Coimbra, Portugal/Pneumology Center, Coimbra University Hospitals, Portugal" "etiqueta" => "<span class="elsevierStyleSup">4</span>" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Correspondence to: Prof. Dra. Lina Carvalho, MD, PhD., Instituto de Anatomia Patológica Faculdade de Medicina; Universidade de Coimbra 3000-054 Coimbra, Portugal. Tel. number: 00351239857762/65 Fax number: 00351239857704." ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Polysomy and amplification of chromosome 7 defined for EGFR gene in squamous cell carcinoma of the lung together with exons 19 and 21 wild type" ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2009-09-18" "fechaAceptado" => "2009-10-07" "PalabrasClave" => array:2 [ "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec160811" "palabras" => array:1 [ 0 => "Carcinoma do pulmão, carcinoma epidermóide, tecido incluído em parafina, EGFR, amplificação, polissomia." ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key-words" "identificador" => "xpalclavsec160810" "palabras" => array:1 [ 0 => "Lung cancer, epidermoid carcinoma, paraffin-embedded tissue, EGFR, gene amplification, gene polysomy." ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "<span class="elsevierStyleSectionTitle">Objectivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">O receptor do factor de crescimento epidérmico (EGFR) está sobreexpresso na maioria dos carcinomas do pulmão de não pequenas células (CPNPC) e é um dos principais alvos específicos dos inibidores da tirosina cinase (TKI) utilizados para o tratamento do CPNPC avançado. Apesar disto, há um considerável número de factores biológicos que também estão associados à resposta dos EGFR-TKIs. Este estudo teve como principal objectivo a pesquisa de mutações somáticas e amplificação do EGFR em casos de carcinoma epidermóide do pulmão. Material e métodos: Secções representativas de carcinoma epidermóide foram seleccionadas de 54 casos em que o tecido estava fixado em formal e incluído em parafina, sendo depois submetidos à construção de TMA. A determinação da expressão proteica do EGFR foi feita por imunoistoquímica (IHQ) (Zymed, laboratórios). A hibridização in situ de fluorescência (FISH) foi realizada com a sonda EGFR LSI / CEP 7 (Vysis; Abbott Molecular, EUA). O ADN genómico foi extraído de 48 casos, amplificado por reacção em cadeia da polimerase (PCR) para pesquisa de mutações nos exões 19 (deleções) e 21 (mutações pontuais). Todos os casos expressaram positividade para a citoqueratina de alto peso molecular e foi observada negatividade para CK7, CD56 e cromogranina.</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A sobreexpressão proteica do EGFR foi identificada em 49 casos, pela aplicação do score de Hirsh/ Cappuzzo (2005). A pesquisa de alterações génicas no cromossoma 7 e do gene EGFR foram analisadas por FISH e de acordo com o método de Cappuzzo (2005), foi identificada alta polissomia em 31 casos e amplificação em 7 casos. Por electroforese capilar, foram detectadas no exão 19 do EGFR: deleções em heterozigotia em 3 dos 48 casos estudados e o exão 21 apresentou-se sempre na sua forma wild-type, quando estudado por enzimas de restrição.</p> <span class="elsevierStyleSectionTitle">Conclusões</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A detecção de deleções e mutações pontuais no EGFR mostrou ser um evento raro no carcinoma epidermóide do pulmão. Apesar de a presença de mutações no EGFR ser um indicador molecular e de sensibilidade eficaz em doentes com CPNPC avançado, submetidos ao tratamento com EGFR-TKIs, é a determinação de amplificações e de polissomias no gene EGFR que melhor traduz a eficácia do tratamento nos doentes com carcinoma epidermóide, quando isolado do grupo de CPNPC.</p>" ] "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Purpose</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The epidermal growth factor receptor (EGFR) is overexpressed in the majority of nonsmall- cell lung cancers (NSCLC) and is a major target specific EGFR tyrosine kinase inhibitors (TKIs) developed and used for the treatment of advanced NSCLC. A number of biological factors are also associated with EGFR-TKIs responsiveness. This study was focused on EGFR somatic mutations and amplifications in squamous cell lung cancer.</p> <span class="elsevierStyleSectionTitle">Material and methods</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Representative sections of squamous cell carcinoma were selected from 54 surgical specimens from formalin-fixed paraffin-embedded tissues and submitted to TMA construction. Determination of EGFR protein expression was done by immunohistochemistry(IHC) (Zymed, Laboratories). Fluorescence in situ hybridization (FISH) was performed with LSI EGFR/CEP 7 (Vysis; Abbott Molecular, USA). Genomic DNA was extracted from 48 cases and exon 19 was amplified by polymerase chain reaction (PCR) for search deletions and point mutations for exon 21. All cases expressed high weigh cytokeratin and were observed negativity for CK7, CD56 and chromogranin.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">EGFR protein overexpression was identified in 49 cases, by the application of Hirsh's scoring system. The chromosome 7 and EGFR gene were analyzed by FISH and scored according to Cappuzzo's method that showed high polysomy in 31 cases and amplification in 7 cases. Deletion in exon 19 of EGFR was detected in 3 cases of 48 samples; the exon 21 of EGFR was expressed in its wild type by RFLP in all cases.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Detection of common EGFR deletion and mutation showed to be a rare event in Squamous cell carcinoma of the lung. While EGFR mutation is the most effective molecular predictor or sensitivity in patients with advanced NSCLC submitted to EGFR-TKIs treatment, amplification and polysomy is the most effective molecular predictor for EGFR-TKIs responsiveness in squamous cell carcinoma, when valida ted isolated from the group of NSCLC.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular predictors of EGFR sensitivity in advanced non-small cell lung cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "X. Zhang" 1 => "A. 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ISSN: 21735115Original language: Portuguese
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