RESUMO
Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Proteínas de Ligação a DNA , Elementos Facilitadores Genéticos/genética , Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fator de Transcrição PAX5/biossíntese , Fator de Transcrição PAX5/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fatores de Transcrição/genéticaRESUMO
Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
Assuntos
Genoma Humano/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Sequência de Aminoácidos , Animais , Proteínas de Transporte/genética , Análise Mutacional de DNA , Humanos , Carioferinas/genética , Dados de Sequência Molecular , Fator 88 de Diferenciação Mieloide/química , Fator 88 de Diferenciação Mieloide/genética , Receptor Notch1/genética , Receptores Citoplasmáticos e Nucleares/genética , Reprodutibilidade dos Testes , Proteína Exportina 1RESUMO
The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Assuntos
Genética Médica/organização & administração , Genoma Humano/genética , Genômica/organização & administração , Cooperação Internacional , Neoplasias/genética , Metilação de DNA , Análise Mutacional de DNA/tendências , Bases de Dados Genéticas , Genes Neoplásicos/genética , Genética Médica/tendências , Genômica/tendências , Humanos , Propriedade Intelectual , Mutação , Neoplasias/classificação , Neoplasias/patologia , Neoplasias/terapiaRESUMO
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Assuntos
Humanos , Pesquisa Biomédica/legislação & jurisprudência , Legislação Médica/tendências , Ética em Pesquisa , Direitos Humanos , Obtenção de Tecidos e Órgãos/legislação & jurisprudênciaRESUMO
The author analyses the implications of cell therapy from a legal study that regulates the use of embryonic material: the regulation of the obtaining of cells, of research with embryos and their research and therapeutic use. There is a detailed look at the provisions in the Convention on Human Rights and Biomedicine of the Council of Europe and concludes that "therapeutic cloning" is not prohibited in our legal regulation.
Assuntos
Transplante de Células/ética , Transplante de Células/legislação & jurisprudência , Clonagem de Organismos , Comércio , Células-Tronco Embrionárias/transplante , Europa (Continente) , Humanos , Indústrias , SociologiaRESUMO
El autor analiza las implicaciones de la terapia celular a partir del estudio jurídico que regula la utilización de materia embrionaria: el régimen de la obtención de las células, de la investigación con embriones y de su creación con fines de investigación y de terapia. Se detiene con minuciosidad en las previsiones del Convenio de Derechos Humanos y Biomedicina del Consejo de Europa, y concluye que la clonación terapéutica no está prohibida en nuestro ordenamiento jurídico (AU)
The author analyses the implications of cell therapy form a legal study that regulates the use of embryonic material: the regulation of the obtaining of cells, of research with embryonic material; the regulation of the obtaining of cells, of research with embryons and their research and therapeutic use. There is a detailed look at the provisions in the Convention of Human Rights and Biomedicine of the Council of Europe and concludes that therapeutic cloning is not prohibited in our legal regulation (AU)
Assuntos
Humanos , Terapia Baseada em Transplante de Células e Tecidos/ética , Temas Bioéticos , Legislação Médica/tendências , Destinação do Embrião/legislação & jurisprudência , Criação de Embriões para Pesquisa/legislação & jurisprudência , Ética em PesquisaRESUMO
The possibility of obtaining stem cells from human embryos has given rise to an intensive legal and ethical debate. In this paper, attention is paid to the normative disparity and ambiguity in Europe. An argument for the need for a minimum legal harmonization is made; and a prudent and flexible way to reach this successfully is suggested. Establishing a common legal framework seems to be the only way to guarantee true competitiveness for the European scientific community.
