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Title:
Non-coding recurrent mutations in chronic lymphocytic leukaemia | Nature
Description:
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. Genomic approaches in more than 500 patients are used to extend the number of chronic lymphocytic leukaemia (CLL) driver alterations, and also identify novel recurrent mutations in non-coding regions, including an enhancer of PAX5 and the 3′ untranslated region of NOTCH1, which lead to aberrant splicing events, increased NOTCH1 protein stability and activity, and an adverse clinical outcome. This paper from the International Cancer Genomic Consortium reports the results of a number of genomic approaches used to characterize chronic lymphocytic leukaemia and its precursor in more than 500 patients. As well as extending the number of chronic lymphocytic leukaemia driver alterations found in the coding portion of the genome, the study identies novel recurrent mutations in non-coding regions, including the 3′ UTR of NOTCH1, which cause aberrant splicing events, an increase in NOTCH1 activity and more aggressive disease, as well as mutations in an enhancer which result in reduced expression of the B-cell-specific transcription factor PAX5.
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crispr-cas9 genome editing permissions reprints nature portfolio privacy policy advertising generating libraries cancer development social media middle row stereotyped b-cell receptors sequence alignment/map format estudis avançats-academia investigators research unit universidad de salamanca-csic carlos lópez-otín rna-seq reads supporting full size image european genome-phenome archive extended data figures high-resolution genomic profiling crispr/cas9-induced mutations crispr/cas9-introduced mutations research nature methods 4 nature methods 9 nature methods 11 nature rev nature genet nature biotechnol nature immunol richter syndrome erin pax5-enhancer-mutated lymphoblastoid recurrently mutated enhancer poor-prognostic stereotyped subsets permissions springerlink instant access extended data fig exome sequencing data genotyping array data chronic lymphocytic leukaemia tumor incidence data b-cell differentiation immunoglobulin-variable-region mutations mónica lópez-guerra universidad de deusto nature 475 nature 464 nature 500 nature 412 nature 499
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headline:Non-coding recurrent mutations in chronic lymphocytic leukaemia
description: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 3â² 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 â¥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. Genomic approaches in more than 500 patients are used to extend the number of chronic lymphocytic leukaemia (CLL) driver alterations, and also identify novel recurrent mutations in non-coding regions, including an enhancer of PAX5 and the 3â² untranslated region of NOTCH1, which lead to aberrant splicing events, increased NOTCH1 protein stability and activity, and an adverse clinical outcome. This paper from the International Cancer Genomic Consortium reports the results of a number of genomic approaches used to characterize chronic lymphocytic leukaemia and its precursor in more than 500 patients. As well as extending the number of chronic lymphocytic leukaemia driver alterations found in the coding portion of the genome, the study identies novel recurrent mutations in non-coding regions, including the 3â² UTR of NOTCH1, which cause aberrant splicing events, an increase in NOTCH1 activity and more aggressive disease, as well as mutations in an enhancer which result in reduced expression of the B-cell-specific transcription factor PAX5.
datePublished:2015-07-22T00:00:00Z
dateModified:2015-10-22T00:00:00Z
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ScholarlyArticle:
headline:Non-coding recurrent mutations in chronic lymphocytic leukaemia
description: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 3â² 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 â¥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. Genomic approaches in more than 500 patients are used to extend the number of chronic lymphocytic leukaemia (CLL) driver alterations, and also identify novel recurrent mutations in non-coding regions, including an enhancer of PAX5 and the 3â² untranslated region of NOTCH1, which lead to aberrant splicing events, increased NOTCH1 protein stability and activity, and an adverse clinical outcome. This paper from the International Cancer Genomic Consortium reports the results of a number of genomic approaches used to characterize chronic lymphocytic leukaemia and its precursor in more than 500 patients. As well as extending the number of chronic lymphocytic leukaemia driver alterations found in the coding portion of the genome, the study identies novel recurrent mutations in non-coding regions, including the 3â² UTR of NOTCH1, which cause aberrant splicing events, an increase in NOTCH1 activity and more aggressive disease, as well as mutations in an enhancer which result in reduced expression of the B-cell-specific transcription factor PAX5.
datePublished:2015-07-22T00:00:00Z
dateModified:2015-10-22T00:00:00Z
pageStart:519
pageEnd:524
sameAs:https://doi.org/10.1038/nature14666
keywords:
Cancer
Science
Humanities and Social Sciences
multidisciplinary
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name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
type:PostalAddress
type:Organization
email:[email protected]
name:ElÃas Campo
affiliation:
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona
address:
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
name:Departament dâAnatomÃa Patològica, MicrobiologÃa i FarmacologÃa, Universitat de Barcelona, Barcelona, Spain
name:Programa Conjunto de BiologÃa Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
name:Department of Experimental and Health Sciences, Research Unit on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain
name:Unidad de Genómica, IDIBAPS, Barcelona, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Servicio de HematologÃa, Hospital ClÃnic, IDIBAPS, Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Institute for Cancer Genetics, Columbia University, New York, USA
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Servicio de HematologÃa, Hospital Universitario Central de Asturias, Oviedo, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Servicio de HematologÃa, Hospital ClÃnic, IDIBAPS, Barcelona, Spain
name:Unidad de Genómica, IDIBAPS, Barcelona, Spain
name:Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), Hospital del Mar Research Institute (IMIM), Barcelona, Spain
name:Institute for Cancer Genetics, Columbia University, New York, USA
name:Programa Conjunto de BiologÃa Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Programa Conjunto de BiologÃa Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
name:Servicio de HematologÃa, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain
name:Centro Nacional de Análisis Genómico, Parc CientÃfic de Barcelona, Barcelona, Spain
name:Servicio de HematologÃa, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del PaÃs Vasco, Bilbao, Spain
name:Programa Conjunto de BiologÃa Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
name:Servicio de HematologÃa, Hospital Universitario Central de Asturias, Oviedo, Spain
name:Unidad de Genómica, IDIBAPS, Barcelona, Spain
name:Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain
name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
name:Departament dâAnatomÃa Patològica, MicrobiologÃa i FarmacologÃa, Universitat de Barcelona, Barcelona, Spain
name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
name:Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del PaÃs Vasco, Bilbao, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Programa Conjunto de BiologÃa Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Institut dâInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
name:Institute of Applied Biosciences, Center for Research and Technology Hellas, Thermi, Greece
name:Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
name:Department of Experimental and Health Sciences, Research Unit on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain
name:Servicio de HematologÃa, Hospital ClÃnico de Valencia, Valencia, Spain
name:Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, Madrid, Spain
name:Department of Experimental and Health Sciences, Research Unit on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain
name:Programa Conjunto de BiologÃa Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, Barcelona, Spain
name:Centro Nacional de Análisis Genómico, Parc CientÃfic de Barcelona, Barcelona, Spain
name:Servicio de HematologÃa, Hospital ClÃnic, IDIBAPS, Barcelona, Spain
name:Departamento de BioquÃmica y BiologÃa Molecular, Instituto Universitario de OncologÃa (IUOPA), Universidad de Oviedo, Oviedo, Spain
name:Unitat de HematologÃa, Hospital ClÃnic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
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