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Characterization of Chronic Lymphocytic Leukemia by Acgh/MLPA

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Characterization of Chronic Lymphocytic Leukemia by Acgh/MLPA UNIVERSIDADE DE LISBOA FACULDADE DE CIÊNCIAS DEPARTAMENTO DE BIOLOGIA VEGETAL Characterization of Chronic Lymphocytic Leukemia by aCGH/MLPA Diana Cristina Antunes Candeias Adão Mestrado em Biologia Molecular e Genética Dissertação orientada por: Professora Doutora Isabel Maria Marques Carreira Professor Doutor Manuel Carmo Gomes 2018 Agradecimentos Começo por agradecer ao CIMAGO e à ACIMAGO por todo o apoio prestado no âmbito do desenvolvimento deste trabalho, tanto a nível logístico como financeiro. Agradeço também ao Laboratório de Citogenética e Genómica e ao Laboratório de Oncologia e Hematologia da FMUC, pelo fornecimento dos equipamentos e bens necessários à realização deste projeto. À Professora Doutora Isabel Marques Carreira, muito obrigada por me permitir desenvolver o meu projeto de tese de mestrado no Laboratório de Citogenética e Genómica da FMUC e por orientar este trabalho. Agradeço tudo o que me ensinou, o apoio e, acima de tudo, o exemplo que é como profissional na área da Genética Humana, que em muito contribuiu para o meu desenvolvimento e crescimento a nível académico e profissional. Ao Professor Doutor Manuel Carmo Gomes, pela sempre célere e incondicional orientação durante este ano. Mostrou-se sempre disponível para responder às minhas dúvidas e questões, e por isso demonstro o meu agradecimento. À Professora Doutora Ana Bela Sarmento Ribeiro, pela proposta que me apresentou para trabalhar no âmbito da Leucemia Linfocítica Crónica, pelo apoio nas correções necessárias, e pela possibilidade que me deu de realizar alguns passos do meu trabalho nas instalações do Laboratório de Oncologia e Hematologia da FMUC. Ao Miguel Pires, por todos os ensinamentos ao nível do trabalho laboratorial, pela enorme disponibilidade e apoio na realização desta tese, bem como pela amizade e conselhos que me deu. À Doutora Ana Cristina Gonçalves, que sempre me ajudou na correção de conteúdos da tese e nas questões relacionadas com as amostras a estudar. Muito obrigada pelo apoio. À Susana Ferreira, Ilda Ribeiro, Mariana Val, Joana Jorge e Raquel Alves, pelo apoio ao nível de aplicação de técnicas e interpretação de resultados, bem como pela amizade. À Drª Amélia Pereira e ao Dr. José Pedro Carda, do Serviço de Medicina do Hospital Distrital da Figueira da Foz e Departamento de Hematologia Clínica dos CHUC, respetivamente, pela disponibilização de amostras para este estudo. Um especial agradecimento a todos os doentes a serem seguidos nos serviços referidos, que aceitaram fornecer as suas amostras e contribuir para o desenvolvimento deste estudo. À equipa técnica da Unidade de Gestão Operacional Citometria do Serviço de Patologia Clínica dos CHUC, que se mostrou sempre prestável na preparação das amostras disponíveis. Apresento um especial agradecimento ao coordenador deste serviço, Professor Doutor Artur Paiva. À restante equipa do Laboratório de Citogenética e Genómica da FMUC, Professora Doutora Joana Barbosa de Melo, Alexandra Marques, Ana Jardim, Cláudia Pais, Lúcia Simões, Patrícia Paiva, Nuno Lavoura, Marta Pinto, Carla Henriques e Sónia Pereira, pela forma como me receberam, por tudo o que me ensinaram ao nível do trabalho deste laboratório e pela amizade. I Às minhas colegas Alexandra Oliveira, Inês Gonçalves, Inês Tavares, Laura Silvério, Luísa Esteves e Mariana Tomás que sempre estiveram disponíveis para discutir ideias, pontos de vista e dar conselhos. Obrigada pelo companheirismo e pelos bons momentos que passámos. À minha colega de Licenciatura Ana Gaspar, pela companhia nas sessões de escrita da tese, pelo apoio e motivação, pela partilha das preocupações e conquistas deste ano e, principalmente, pela amizade que mantemos. Ao Zé Miguel, por me ter ajudado a manter a motivação para a tese até ao fim, e por ouvir sempre os meus relatos sobre o dia-a-dia do laboratório! Por último, quero agradecer a toda a minha família pelo apoio que me deram, especialmente aos meus pais e à minha irmã, pois sempre me motivaram e acreditaram que eu seria capaz de chegar onde cheguei. Para vocês, um beijinho grande! II Resumo Palavras-chave: Leucemia Linfocítica Crónica; CNVs; iFISH; aCGH; MLPA A Leucemia Linfocítica Crónica (LLC) é o tipo de leucemia mais frequente na população adulta de países ocidentais, cuja idade média ao diagnóstico varia entre os 67 e os 72 anos. É caracterizada pela expansão clonal e acumulação de linfócitos B neoplásicos no sangue periférico e na medula óssea, resistentes à apoptose e imunologicamente incompetentes.. Estas células têm também a capacidade de infiltrar outros órgãos como o baço ou o fígado. Os indivíduos com LLC apresentam diversas alterações genómicas características, que estão associadas a diferentes subtipos da doença com diferentes comportamentos biológicos e clínicos. Os dois principais subtipos de LLC são caracterizados pela ausência ou presença de genes mutados na região codificante da cadeia pesada da região variável das imunoglobulinas (IGHV), sendo que o estado não mutado destes genes é o que constitui a situação de doença mais agressiva. A sobre- expressão dos genes CD38 e ZAP70 é um parâmetro que auxilia na estratificação de doentes em grupos com diferentes prognósticos que, possivelmente, necessitam de diferentes estratégias terapêuticas. Para além destes marcadores, podem ocorrer alterações epigenéticas; mutações somáticas nos genes MYD88, NOTCH1, SF3B1 e TP53; variações no número de cópias (CNVs) de segmentos de DNA; trissomias 9, 12, 18 e 19, e translocações que envolvam o locus IGH. Uma CNV é um segmento de DNA com pelo menos 1 kilobase (Kb) que apresenta variação no número das suas cópias (perda ou ganho) relativamente a um DNA de referência de um indivíduo saudável. Uma translocação recíproca é uma troca de posições entre dois segmentos de DNA, entre cromossomas não homólogos. Ao longo das últimas décadas estas alterações têm vindo a ser detetadas, na prática clínica, pela técnica de Hibridização Fluorescente In Situ aplicada a células em interfase (iFISH). A iFISH permitiu realizar uma melhor estratificação destes doentes em diferentes grupos, aos quais são associados diferentes prognósticos. Estes grupos baseiam-se na presença de: (i) deleção em 13q como única alteração; (ii) nenhuma alteração; (iii) trissomia 12; (iv) deleção em 11q e (v) deleção em 17p (grupos apresentados por ordem crescente de pior prognóstico previsto), sendo (i) o grupo de melhor prognóstico e (v) o de pior prognóstico. Posteriormente, foram adicionadas a este painel sondas para a deteção da deleção em 6q e translocações do gene IGH. No entanto, devido à heterogeneidade biológica e clínica desta doença, existe consciência da importância de procurar novas CNVs com possível valor como marcadores de prognóstico. De facto, nem todas as terapias desenvolvidas são aplicáveis a doentes com diferentes tipos de alterações. Um exemplo disso é o caso dos doentes com a del(17p) e/ou mutação do gene TP53. Neste grupo de doentes, a quimioimunoterapia é altamente desaconselhada devido ao facto de esta recorrer a agentes dependentes da atividade da proteína p53 que, por estar ausente e/ou mutada nos doentes com del(17p) e/ou mutação do gene TP53, impede que esta terapêutica conduza a resultados favoráveis. Assim sendo, os doentes com estas alterações são candidatos a terapêutica dirigida recorrendo a inibidores da via BTK, como o ibrutinib. Com este trabalho piloto, o nosso grupo realizou a caracterização de uma coorte de 20 doentes com LLC, ao nível do seu conteúdo em CNVs. Para tal, aplicámos as técnicas de Amplificação Multiplex de Sondas Dependente de Ligação (MLPA) e arrays de Hibridização Genómica Comparativa (aCGH), após extração de DNA a partir de células mononucleares do sangue periférico (PBMCs), e tendo em conta o genoma de referência GRCh37/hg9 (Genome Reference Consortium Human Build 37/human genome 19). Após a obtenção de resultados, fizemos um estudo de sobrevivência global ao longo de um período médio de follow-up de 114 meses, aplicando o método estatístico de Kaplan-Meier. Com base nos resultados de MLPA, dividimos as amostras em duas categorias: um grupo com doentes que tinham ≥2 alterações e outro com doentes que tinham <2 alterações. Interpretámos, também, a distribuição de algumas das alterações que detetámos em maior III frequência: del(11q), del(14q), e mutação no gene NOTCH1, em doentes agrupados de acordo com o seu estadiamento pelos sistemas Binet e Rai (sistemas de classificação de estadiamento específicos para LLC). Para tal, aplicámos o teste qui-quadrado de Pearson. Relativamente à análise de sobrevivência, apesar de os nossos resultados não terem apresentado significância estatística, estes sugerem que existe uma associação entre o aumento no número de alterações genómicas que um doente tem e a diminuição na taxa de sobrevivência. Quanto às prevalências das alterações del(11q), del(14q) e mutação do gene NOTCH1, verificámos que estas são significativamente mais altas em doentes que se encontram num estadiamento intermédio/alto de risco de doença do que em doentes com estadiamento de baixo risco, o que sugere a sua importância como marcadores de mau prognóstico. Isto é algo que já foi previamente descrito para a del(11q) e para a mutação em NOTCH1 mas, tanto quanto é do nosso conhecimento, é algo que não foi ainda visto, por outros grupos, para doentes com a alteração del(14q). Para além das conclusões tiradas relativamente às alterações genómicas em doentes com esta neoplasia, foi-nos possível fazer algumas comparações entre as técnicas aplicadas. Apresentamos, também, uma comparação
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