ABSTRACT
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.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation/genetics , 3' Untranslated Regions/genetics , Alternative Splicing/genetics , B-Lymphocytes/metabolism , Carrier Proteins/genetics , Chromosomes, Human, Pair 9/genetics , DNA Mutational Analysis , DNA, Neoplasm/genetics , DNA-Binding Proteins , Enhancer Elements, Genetic/genetics , Genomics , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , PAX5 Transcription Factor/biosynthesis , PAX5 Transcription Factor/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Transcription Factors/geneticsABSTRACT
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.
Subject(s)
Genome, Human/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation/genetics , Amino Acid Sequence , Animals , Carrier Proteins/genetics , DNA Mutational Analysis , Humans , Karyopherins/genetics , Molecular Sequence Data , Myeloid Differentiation Factor 88/chemistry , Myeloid Differentiation Factor 88/genetics , Receptor, Notch1/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Reproducibility of Results , Exportin 1 ProteinABSTRACT
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.
Subject(s)
Genetics, Medical/organization & administration , Genome, Human/genetics , Genomics/organization & administration , International Cooperation , Neoplasms/genetics , DNA Methylation , DNA Mutational Analysis/trends , Databases, Genetic , Genes, Neoplasm/genetics , Genetics, Medical/trends , Genomics/trends , Humans , Intellectual Property , Mutation , Neoplasms/classification , Neoplasms/pathology , Neoplasms/therapyABSTRACT
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.
Subject(s)
Cell Transplantation/ethics , Cell Transplantation/legislation & jurisprudence , Cloning, Organism , Commerce , Embryonic Stem Cells/transplantation , Europe , Humans , Industry , SociologyABSTRACT
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.