title: Non-coding recurrent mutations in chronic lymphocytic leukaemia.
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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Beà
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Valdés-Mas
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gutiérrez-Abril
authors.affiliation: Departament d'Anatomía Patològica, Microbiología i Farmacología, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Munar
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: Rubio-Pérez
authors.affiliation: Unidad de Genómica, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: Servicio de Hematología, Hospital Clínic, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Tycho
authors.initials: T
authors.lastname: Baumann
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Renée
authors.initials: R
authors.lastname: Beekman
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York 10032, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Belver
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Carrio
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Clot
authors.affiliation: Servicio de Hematología, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Colado
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Costa
authors.affiliation: Servicio de Hematología, Hospital Clínic, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Unidad de Genómica, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Enjuanes
authors.affiliation: Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), Hospital del Mar Research Institute (IMIM), 08003 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York 10032, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Josep L
authors.initials: JL
authors.lastname: Gelpí
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: González
authors.affiliation: Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: González
authors.affiliation: Servicio de Hematología, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: González
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Servicio de Hematología, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Hernández-Rivas
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martín-García
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del País Vasco, 48007 Bilbao, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Nicolás
authors.affiliation: Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.affiliation: Servicio de Hematología, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
authors.forename: Ángel R
authors.initials: ÁR
authors.lastname: Payer
authors.affiliation: Unidad de Genómica, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Magda
authors.initials: M
authors.lastname: Pinyol
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, 28029 Madrid, Spain.
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Diana A
authors.initials: DA
authors.lastname: Puente
authors.affiliation: Departament d'Anatomía Patològica, Microbiología i Farmacología, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Queirós
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Quesada
authors.affiliation: Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del País Vasco, 48007 Bilbao, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Romeo-Casabona
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Royo
authors.affiliation: Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Romina
authors.initials: R
authors.lastname: Royo
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Rozman
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Russiñol
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverría
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, 57001 Thermi, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, The Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Tamborero
authors.affiliation: Servicio de Hematología, Hospital Clínico de Valencia, 46010 Valencia, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Terol
authors.affiliation: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute, 28029 Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: López-Bigas
authors.affiliation: Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Torrents
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, 08028 Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Servicio de Hematología, Hospital Clínic, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, 08036 Barcelona, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic / Q000235:genetics; D023281:Genomics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; C112476:ARID1A protein, human; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D051881:Receptor, Notch1; D014157:Transcription Factors; C102796:ZMYM3 protein, human; C570380:ZNF292 protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11