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Francine Blumental De Abreu

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Francine Blumental De Abreu VARIAÇÃO NO NÚMERO DE CÓPIAS GENÔMICAS NA AVALIAÇÃO DE GENES PRINCIPAIS DE PREDISPOSIÇÃO EM PACIENTES COM SÍNDROME DE MAMA-CÓLON TRIADOS PARA MUTAÇÕES NOS GENES BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 FRANCINE BLUMENTAL DE ABREU Tese apresentada à Fundação Antônio Prudente para obtenção do Título de Doutor em Ciências Área de concentração: Oncologia Orientadora: Profª Dra. Silvia Regina Rogatto São Paulo 2012 FICHA CATALOGRÁFICA Preparada pela Biblioteca da Fundação Antônio Prudente Abreu, Francine Blumental de Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com síndrome de mama- cólon triados para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 / Francine Blumental de Abreu – São Paulo, 2012. 245p. Tese (Doutorado)-Fundação Antônio Prudente. Curso de Pós-Graduação em Ciências - Área de concentração: Oncologia. Orientadora: Silvia Regina Rogatto Descritores: 1. SÍNDROME DE LYNCH. 2. NEOPLASIAS DA MAMA. 3. VARIAÇÃO DO NÚMERO DE CÓPIA DO DNA. 4. HIBRIDIZAÇÃO GENÔMICA COMPARATIVA. DEDICATÓRIA A minha família!!!! AGRADECIMENTOS À minha família... Edilucia (II:5) e Antonio (II:6) por serem mais do que pais, por serem mais do que amigos, por serem os meus super heróis! Obrigada pelos abraços, pelas palavras de apoio e de ensinamento, pelo carinho, pelo amor incondicional! Obrigada por estarem sempre disponíveis, por estenderem as mãos depois de uma “rasteira” da vida, por enxugarem as minhas lágrimas! Obrigada principalmente por me fazerem acreditar que momentos difíceis existem, mas ao lado de vocês, eles se tornam mais fáceis. Obrigada por existirem, obrigada simplesmente por tudo! Obrigada!! Amo vocês!!! Luciana (II:7) pelas palavras de apoio e de ensinamento, pelo carinho e pelo amor!! Obrigada por também estender as mãos depois de uma “rasteira” da vida! Obrigada por fazer parte da minha vida! Obrigada!! Amo você!!! Patrícia (III:5) pelo carinho e pelo amor!! Obrigada por me ouvir! Obrigada pelos conselhos e pelos “puxões de orelha”! Obrigada por cuidar da nossa mãe com tanto carinho e amor! Te amo minha irmã!! Marcelo (III:7) (in memoriam), por estar presente (não de corpo, mas de alma) em todos os momentos da minha vida! Obrigada pelos sonhos!! Obrigada pelo perfume!! Te amo!! Leozinho (III:8) pelos abraços apertados, pelos beijos “do gordo” e pelo brilho nos olhos quando me vê! Obrigada por demonstrar amor e carinho da forma mais sincera e pura! Te amo meu irmãozinho!! Lucy (II:9) e David (II:8) pelo imenso carinho! Obrigada pelas palavras de amigo, ou melhor, pelas palavras de “mãe e pai”! Obrigada pela força e confiança! Amo vocês!! À minha orientadora... Dra Silvia Regina Rogatto pela oportunidade, atenção, preocupação, confiança e ensinamentos durante todos esses anos. Obrigada!! Aos alunos e funcionários do Laboratório Neogene. Obrigada especial aos alunos Fernanda, Hellen e Mateus não só pelos ensinamentos e ajuda na realização desse trabalho, mas também pela amizade! Aos pesquisadores... Dra Ana Krepischi por ter me ajudado nos experimentos e análises de CGH array. Obrigada pelas palavras, abraços, carinho e disponibilidade nos momentos que mais precisei. Obrigada pela confiança! Dr Benedito pela disponibilidade e atenção durante a execução deste trabalho. Obrigada pelo apoio e confiança! Dra Carla Rosemberg pelo conselho e abraço no momento que mais precisei. Muito obrigada! Dra Dirce por disponibilizar seu laboratório, seus alunos e funcionários no auxílio de alguns experimentos. Obrigada pela confiança! Dra Érika pela disponibilidade, atenção e carinho. Obrigada por responder todos os meus e-mails com rapidez e eficiência! Dra Maria Isabel por me ajudar na convocação de pacientes e pela disponibilidade. Obrigada, principalmente, pela confiança! Dr Rafael pela disponibilidade e atenção durante os momentos finais da tese. Obrigada! Agradecimento especial à Dra Ana Krepischi, Dra Dirce, Dr Fernando e Dra Maria Isabel por confiarem em mim e por me ajudarem na realização de um sonho! Obrigada do fundo meu coração!! Aos meus amigos... “E o que importa não é o que você tem na vida, mas quem você tem na vida. E que bons amigos são a família que nos permitiram escolher” (autor desconhecido) Elô e Carol por serem mais do que amigas irmãs! Obrigada pelos queijos e vinhos, cervejas, piadas, conselhos, baladas, filmes....obrigada por me fazerem chorar de tanto rir....obrigada por enxugarem as minhas lágrimas....obrigada por existirem e fazerem parte da minha vida!!! Amo vocês! Eliane, Renata e Fabíola por estarem perto mesmo estando longe! Obrigada pelos e-mails, telefonemas, mensagens, visitas! Obrigada pelos ensinamentos!! Obrigada pelo carinho!! Amo vocês! Tati e Amanda pelo carinho, pelos conselhos e abraços! Obrigada por segurarem minhas mãos nos momentos mais difíceis! Obrigada pelos “puxões de orelha”! Obrigada por me fazerem sorrir!! Amo vocês! Aos alunos e funcionários do laboratório LGBM... Bianca, Bruna, Cris, Dani, Elisa, Felipe, Gi e Márcia, pela disponibilidade em me ajudar na execução de alguns experimentos. Obrigada principalmente pelo carinho, pelos fortes abraços, pelos conselhos!!! Vocês são pessoas muito especiais!! Ao hospital AC Camargo... Funcionários do Banco de Macromoléculas (Ana, Eloisa e Louise) pela ajuda na aquisição das amostras e ajuda na pesquisa de amostras. Obrigada especial a Ana e Eloisa por estarem do meu lado como amigas! Funcionários da Biblioteca (Jefferson e Sueli) pelo auxílio durante as pesquisas bibliográficas, pesquisa de artigos científicos e revisão deste trabalho. Obrigada pelo carinho com que me trataram todos esses anos! Funcionárias da Pós-graduação (Ana, Luciana e Vanusa) pelo auxílio oferecido no decorrer desses anos. Funcionários do SAME por separar os prontuários dos pacientes dessa pesquisa. As Instituições de Fomento... FAPESP e CNPq pelo suporte financeiro. O valor das coisas não está no tempo que elas duram, mas na intensidade com que acontecem. Por isso existem momentos inesquecíveis, coisas inexplicáveis e pessoas incomparáveis. (Fernando Pessoa) RESUMO Abreu FB. Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com Síndrome de Mama-Cólon triados para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 e MSH2. São Paulo; 2012. [Tese de Doutorado-Fundação Antônio Prudente]. A Síndrome de Lynch (SL) é uma síndrome hereditária de predisposição ao câncer colorretal associado com um risco aumentado de desenvolvimento de tumores extracolônicos. No Brasil, o carcinoma mamário é o tumor extracolônico de maior inciência na SL. Neste estudo, 65 pacientes foram divididos em três grupos: 1 e 2, composto por 59 pacientes negativos para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 e MSH2 e, 3, formado por 6 pacientes com mutação em um desses genes. O grupo 1 apresentava 26 pacientes com câncer de mama ou colorretal, grupo 2 apresentava 33 pacientes com câncer de mama e colorretal. As variações no número de cópias genômicas (CNVs) foram investigadas pelo método de CGH array utilizando a plataforma de 4x180K (Agilent Techonologies). Os dados foram extraídos no Software Feature Extraction e analisados no Software Genomic Workbench 5.0. Para a análise foram utilizados o algoritmo estatístico ADM-2, threshold 6,7 e -0,3≤log2≥0,3 para determinar as regiões de ganhos e perdas genômicas. As alterações foram comparadas com o banco de dados DGV e com um banco de dados específico da população brasileira (grupo referência). Na análise de aCGH, foram identificadas 451 alterações, sendo 161 do grupo 1, 257 do grupo 2 e 33 do grupo 3. Após a comparação com o banco de dados da população brasileira, as alterações foram classificadas em comuns, raras e novas raras. Foram consideradas como relevantes para o estudo apenas as CNVs raras, identificadas em 1% da população de referência, e as CNVs novas raras, ausentes tanto na população de referência como no banco de dados DGV. Entre os pacientes sem mutação, foram identificadas CVNs novas raras comuns e exclusivas aos grupo 1 e 2. O gene SLC38A6 foi identificado em duas pacientes do grupo 1 e uma do grupo 2. É um gene envolvido no transporte de glutamina, um aminoácido envolvido em muitas funções, entre elas produção de ATP. Os genes envolvidos em ganho genômico, GRM1 e TMPRSS3 (exclusivos do grupo 1) e FOXP1 e BLM (exclusivos do grupo 2) têm potencial para contribuir para o desenvolvimento tumoral. Na análise familial, foram identificados genes e microRNA envolvidos em CNVs raras e novas raras com potencial para o desenvolvimento e predisposição ao câncer de mama e colorretal. A perda genômica no gene ROBO1 foi identificada em duas pacientes (grupo 1 e 2) e em seus respectivos familiares. Essa alteração foi confirmada por qPCR e a baixa expressão da proteína ROBO1 foi associada com pior prognóstico da doença. Os resultados sugerem que determinadas alterações genômicas tem potencial associação com a predisposição hereditária tumores de mama e colorretal. SUMMARY Abreu FB. [Analysis of copy number alterations in patients with breast and colorectal cancer syndrome that are negative for BRCA1, BRCA2, TP53, CHEK2, MLH1 and MSH2 mutations]. São Paulo, 2012. [Tese de Doutorado-Fundação Antônio Prudente]. Lynch syndrome (LS) is a hereditary colorectal cancer syndrome associated to an increased risk to develop extracolonic tumors. In Brazil, breast cancer is the extracolonic tumor with more incidence among LS patients. On this study, 65 patients were dividided into three groups: 1 and 2, composed of 59 patients negative for BRCA1, BRCA2, TP53, CHEK2, MLH1 and MSH2 mutations and, 3, composed of six patients with a mutation in one of these genes. Group 1 had 26 patients with breast or colorectal cancer and group 2 had 33 patients with breast and colorectal cancer. Copy number variations (CNVs) were investigated by CGH array using 4x180K platform (Agilent Techonologies). Data were extracted by Feature Extraction Software and analyzed by Genomic Workbench 5.0 Software, using the ADM2 algorithm with a 6.7 threshold and absolute log ratio filter of -0,3≤log2≥0,3 to identify genomic losses and gains.
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