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Análise Do Perfil De Expressão Gênica De Carcinoma Ductal in Situ E Invasivo Em Tumores De Mama Através Da Técnica De Microarray

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Análise Do Perfil De Expressão Gênica De Carcinoma Ductal in Situ E Invasivo Em Tumores De Mama Através Da Técnica De Microarray ANÁLISE DO PERFIL DE EXPRESSÃO GÊNICA DE CARCINOMA DUCTAL IN SITU E INVASIVO EM TUMORES DE MAMA ATRAVÉS DA TÉCNICA DE MICROARRAY NÁDIA PEREIRA DE CASTRO Tese apresentada à Fundação Antônio Prudente para obtenção do título de Doutor em Ciências Área de Concentração: Oncologia Orientadora: Dra. Dirce Maria Carraro Co-Orientadora: Dra. Anamaria Aranha Camargo São Paulo 2008 Livros Grátis http://www.livrosgratis.com.br Milhares de livros grátis para download. FICHA CATALOGRÁFICA Preparada pela Biblioteca da Fundação Antônio Prudente Castro, Nadia Pereira de Análise do perfil de expressão gênica de carcinoma ductal in situ e invasivo em tumores de mama através da técnica de microarray / Nadia Pereira de Castro -- São Paulo, 2008. 174p. Tese (doutorado)-Fundação Antônio Prudente. Curso de Pós-Graduação em Ciências-Área de concentração: Oncologia. Orientadora: Dirce Maria Carraro. Descritores: 1. MICRODISSECÇÃO A LASER. 2. CARCINOMA DUCTAL DE MAMA/genética. 3. PERFIL DA EXPRESSÃO GÊNICA. 4. ANALISES MICROARRAY. DEDICATÓRIA Dedico esta conquista… À Deus pela vida plena e por tudo que sou. Por Seu imensurável amor e cuidado. Pela paz e esperança. Meu criador, mantenedor e amigo. Aos meus pais queridos (Rubles e Neide) pela dedicação, amor, apoio incondicional e por nunca medirem esforços para a minha formação. Aos melhores irmãos do mundo (Rômulo e Rener) pela atenção, companheirismo e cuidado. Vocês são a base das minhas conquistas. Amo vocês!! AGRADECIMENTOS ESPECIAIS Agradeço especialmente... À minha avó (Maria) pelo apoio e cuidado. Aos meus queridos tios (Vanderlei e Sônia) e primos (Vanderson e Emerson) por me acolherem com tanto carinho e dedicação. Ao meu namorado (Rodrigo) pela paciência e compreensão. Aos meus amigos pela atenção, disponibilidade em ajudar, confiança e amizade. Obrigada por acreditarem em mim! AGRADECIMENTOS À minha orientadora Dra. Dirce pela confiança, ensinamentos e oportunidade de crescer. À minha co-orientadora Dra. Anamaria Camargo pela atenção, sugestões e leitura crítica da tese. Ao Laboratório de Biologia Molecular do Hospital A.C. Camargo pelo bom ambiente de trabalho. À Maria Cristina Rangel (amiga de todas as horas, por sempre me ouvir, me ajudar, por se importar e acreditar. Muuuiiito obrigada friend por tudo o que fez por mim, vou sempre me lembrar com carinho tudo o que passamos juntas), Sabrina Daniela (amiga do coração, muito obrigada pelo carinho, atenção, apoio, incentivo, conselhos, por acreditar em mim. Obrigada pela ajuda indispensável com as proteínas e o TMA. Você é única Sassá!), Mev (pelo companherismo, incentivo e convivência. Tu eres buena gente!!) Mariana Maschietto (pela amizade, atenção, sempre pronta a ajudar, obrigada Ma, você é muito querida!), Thiago F. Saraiva (pela amizade, risadas, bolos, corridas no parque e disponibilidade em ajudar nos experimentos. Obrigada Fo!), Jane Kaiano e Louise D. Mota (obrigada pela dedicação em ensinar e ajuda fundamental nos experimentos. Sou muito grata!), Elen Bastos (pela amizade, receitas vegetebas, momento esporte, viagens, atenção e ajuda com as “bolinhas“. Obrigada EB!), Paulo Pineda (pela atenção, paciência, pelas amostras e géis. Valeu Pol!), Reimar Padovani (pelas risadas e ajuda), Jamila (pela atenção e carinho), Elisa (pela prontidão em ouvir e ajudar), Adriana (pela atenção e ajuda), Laura (pelo sorriso e compreensão), Aderbal (pelas risadas), Waleska (Sempre prestativa e amável. Apesar da curta passagem, foi muito bom tê-la conosco), Wilson (pelos momentos de descontração e conselhos) Gustavo (obrigada pela companhia nas corridas, bom humor e atenção), Eloísa (sempre disposta a ajudar, sorridente e querida), Luana e Rafael (pela ajuda com o Bionalyser), Vera (pelos bolos!) Alexandre (o dermatologista do Lab, sempre prestativo). À amiga e 2 vezes vizinha Fernanda Ayala, pela consideração, amizade, pelas conversar sempre produtivas. Gosto muito de você Fê!! Obrigada pessoal por participarem desta etapa da minha vida. Ao laboratório de Biologia Computacional do Hospital A. C. Camargo, à Dra Helena P. Brentani (pela disponibilidade em ensinar e ajudar), Luiz Paulo Camargo (obrigada pela amizade, atenção, momentos de degustação -que saudade daquele peixe- pela prontidão em ajudar sempre, até nas análises!), Artur Fabri (pela atenção, amizade, pela ‘chavinha´), Diogo Patrão (pelos clusters, página da web, ajuda com as análises), e César Torres (pelas análises e atenção). Obrigada pela análise da qualidade das lâminas de cDNA microarray. Aos pesquisadores do IME-USP, Eduardo Jordão Neves e Lucas (pela dedicação e prontidão em ajudar) por realizarem as análises estatísticas e computacionais dos dados de microarray. Obrigada pela paciência e valiosa colaboração nesse trabalho. Ao Instituto Ludwig de Pesquisa Sobre o Câncer - São Paulo, na pessoa da diretora e querida professora Dra. Luisa Villa e à todos do Instituto pela ajuda, pelo convívio e amizades conquistadas. Ao Hospital A.C. Camargo e Fundação Antônio Prudente, São Paulo, na pessoa do diretor Professor Dr. Ricardo Brentani. Ao Dr. Fernando, Isa, Cynthia, Hugo, Renata, André Abreu do departamento de Anatomia Patológica do Hospital A.C. Camargo que se envolveram neste trabalho e me ajudaram com as microdissecções a laser, diagnóstico das lâminas e retirada das amostras no banco de tumores. À Miyuki Silva e Severino Silva pelo trabalho tão cuidadoso com as amostras. Ao José Ivanildo Neves pela prontidão em ajudar e realizar as reações imunohistoquímicas. À Sabrina Daniela pelo envolvimento e dedicação na leitura dos TMAs e ao Dr. João Gonçalves pelas análises estatísticas. Aos médicos do Departamento de Mastologia pelas amostras coletadas para o banco de tumores. Em especial, o Dr Mourão e a Dra Socorro pelos ensinamentos. Aos responsáveis da Pós-Graduação, especialmente Dr. Luiz Fernando Lima Reis, Ana Maria Kurinari e Luciane Pitombeira. Pela paciência, compreensão e cuidado dispensados. À Biblioteca da Fundação Antônio Prudente pelo acervo e auxílio nas pesquisas bibliográficas, em especial Suely pela ajuda na elaboração da versão final da tese. As meninas da biblioteca: Rosinéia Aguiar Carneiro e Francyne Pólen G. Lima sempre tão dispostas e eficientes. Não tenho palavras para agradecer !! À todos os funcionários do SAME pela disposição e ajuda, em especial a Dona Hirde Contesini pela simpatia e atenção. À FAPESP pela bolsa concedida e suporte financeiro para o desenvolvimento desse projeto. Aos pacientes e seus familiares por permitirem a realização desta pesquisa. E a todas as outras pessoas que, direta ou indiretamente, me auxiliaram e contribuíram na realização deste estudo. Deixo aqui os meus sinceros agradecimentos. Este trabalho é o resultado de todos vocês !! RESUMO Castro NP. Análise do perfil de expressão gênica de carcinoma ductal in situ e invasivo em tumores de mama através da técnica de microarray. São Paulo; 2008. [Tese de Doutorado-Fundação Antônio Prudente]. O câncer de mama está entre as neoplasias de maior incidência e é responsável pela alta taxa de mortalidade entre as mulheres no mundo todo. O carcinoma ductal é o tipo histológico mais freqüente. O carcinoma ductal in situ (DCIS) inclui um grupo de tumores de mama pré-invasivos com potencial maligno distinto, podendo progredir rapidamente para carcinoma invasivo ou não apresentar evolução durante um longo período da doença. Atualmente, um dos maiores desafios na pesquisa molecular nessa área é identificar genes que possam predizer o risco de progressão para doença invasiva e de marcadores de prognósticos. Neste estudo foram analisados 40 casos de mama, sendo 5 amostras de tecido de mamário não neoplásico (N), 16 casos de amostras pareadas de carcinoma ductal (in situ e invasivo), 5 DCIS puro, 9 DCIS coexistindo com o componente invasor (DCIS/IDC) e 5 carcinomas ductais invasivos (IDC). Os RNAs provenientes das células epiteliais microdissecadas foram amplificados e hibridizados pelo sistema inverso de incorporação de fluoróforos (Dye swap) em duas plataformas distintas de cDNA microarray. Uma contendo 4.608 seqüências de cDNA correspondentes a genes humanos (4.8k) e outra contendo 390 genes pertencentes as vias de sinalização WNT, PI3K e processo EMT (Transição Epitélio-Mesênquima). Dois delineamentos experimentais foram usados: comparação entre lesões in situ e invasivo da mesma amostra (DCIS e IDC); e comparação de grupos de lesões que mimetizam a progressão de câncer ductal de mama, utilizando amostras independentes [células epiteliais de mama capturadas de amostra não neoplásica (N), células tumorais capturadas das lesões: DCIS puro, DCIS/IDC e IDC]. Na plataforma 4.8K, 16 amostras pareadas foram usadas para comparar o padrão de expressão de células tumorais do DCIS e IDC de uma mesma paciente. Foram identificados 33 genes diferencialmente expressos (t de Student – Fold > ⎜1,5⎥ e pvalor<0,01), sendo genes candidatos a estarem envolvidos na transição do DCIS para o IDC. Para 4 (LUM, RDH-E2, CXCL13 e POSTN) de 8 genes selecionados foi confirmada expressão diferencial por RT-PCR quantitativo (qRT-PCR). Dois genes (LUM e CRABP2) com maior expressão nas amostras IDC foram selecionados para verificar associação com outros marcadores moleculares e/ou dados clinicopatológicos por Tissue Microarray. A expressão da proteína LUM se mostrou associada positivamente com as CKs 5/6, CK 14, CK8 e 18 e o grupo super-expressão do HER2/neu, enquanto que a expressão da proteína CRABP-2 se mostrou associada positivamente com ER, PR, CK8, CK18, luminal A, p53 e negativamente com a CK14. Buscando caracterizar os aspectos
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