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Non-coding recurrent mutations in chronic lymphocytic leukaemia

Author

Listed:
  • Xose S. Puente

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Silvia Beà

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Rafael Valdés-Mas

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Neus Villamor

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Jesús Gutiérrez-Abril

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • José I. Martín-Subero

    (Departament d’Anatomía Patològica, Microbiología i Farmacología, Universitat de Barcelona)

  • Marta Munar

    (Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona)

  • Carlota Rubio-Pérez

    (Research Unit on Biomedical Informatics, Universitat Pompeu Fabra)

  • Pedro Jares

    (Unidad de Genómica, IDIBAPS)

  • Marta Aymerich

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Tycho Baumann

    (Servicio de Hematología, Hospital Clínic, IDIBAPS)

  • Renée Beekman

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Laura Belver

    (Institute for Cancer Genetics, Columbia University)

  • Anna Carrio

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Giancarlo Castellano

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Guillem Clot

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Enrique Colado

    (Servicio de Hematología, Hospital Universitario Central de Asturias)

  • Dolors Colomer

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Dolors Costa

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Julio Delgado

    (Servicio de Hematología, Hospital Clínic, IDIBAPS)

  • Anna Enjuanes

    (Unidad de Genómica, IDIBAPS)

  • Xavier Estivill

    (Center for Genomic Regulation (CRG), Pompeu Fabra University (UPF), Hospital del Mar Research Institute (IMIM))

  • Adolfo A. Ferrando

    (Institute for Cancer Genetics, Columbia University)

  • Josep L. Gelpí

    (Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona)

  • Blanca González

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Santiago González

    (Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona)

  • Marcos González

    (Servicio de Hematología, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC)

  • Marta Gut

    (Centro Nacional de Análisis Genómico, Parc Científic de Barcelona)

  • Jesús M. Hernández-Rivas

    (Servicio de Hematología, IBSAL-Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC)

  • Mónica López-Guerra

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • David Martín-García

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Alba Navarro

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Pilar Nicolás

    (Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del País Vasco)

  • Modesto Orozco

    (Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona)

  • Ángel R. Payer

    (Servicio de Hematología, Hospital Universitario Central de Asturias)

  • Magda Pinyol

    (Unidad de Genómica, IDIBAPS)

  • David G. Pisano

    (Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute)

  • Diana A. Puente

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Ana C. Queirós

    (Departament d’Anatomía Patològica, Microbiología i Farmacología, Universitat de Barcelona)

  • Víctor Quesada

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Carlos M. Romeo-Casabona

    (Cátedra Inter-Universitaria de Derecho y Genoma Humano, Universidad de Deusto, Universidad del País Vasco)

  • Cristina Royo

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Romina Royo

    (Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona)

  • María Rozman

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

  • Nuria Russiñol

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Itziar Salaverría

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Kostas Stamatopoulos

    (Institute of Applied Biosciences, Center for Research and Technology Hellas)

  • Hendrik G. Stunnenberg

    (Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen)

  • David Tamborero

    (Research Unit on Biomedical Informatics, Universitat Pompeu Fabra)

  • María J. Terol

    (Servicio de Hematología, Hospital Clínico de Valencia)

  • Alfonso Valencia

    (Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Spanish National Bioinformatics Institute)

  • Nuria López-Bigas

    (Research Unit on Biomedical Informatics, Universitat Pompeu Fabra)

  • David Torrents

    (Programa Conjunto de Biología Computacional, Barcelona Supercomputing Center (BSC), Institut de Recerca Biomèdica (IRB), Spanish National Bioinformatics Institute, Universitat de Barcelona)

  • Ivo Gut

    (Centro Nacional de Análisis Genómico, Parc Científic de Barcelona)

  • Armando López-Guillermo

    (Servicio de Hematología, Hospital Clínic, IDIBAPS)

  • Carlos López-Otín

    (Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo)

  • Elías Campo

    (Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona)

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.

Suggested Citation

  • Xose S. Puente & Silvia Beà & Rafael Valdés-Mas & Neus Villamor & Jesús Gutiérrez-Abril & José I. Martín-Subero & Marta Munar & Carlota Rubio-Pérez & Pedro Jares & Marta Aymerich & Tycho Baumann & Ren, 2015. "Non-coding recurrent mutations in chronic lymphocytic leukaemia," Nature, Nature, vol. 526(7574), pages 519-524, October.
    • Handle: RePEc:nat:nature:v:526:y:2015:i:7574:d:10.1038_nature14666
    DOI: 10.1038/nature14666
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    Citations

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    Cited by:

    1. Sophie A. Herbst & Mattias Vesterlund & Alexander J. Helmboldt & Rozbeh Jafari & Ioannis Siavelis & Matthias Stahl & Eva C. Schitter & Nora Liebers & Berit J. Brinkmann & Felix Czernilofsky & Tobias R, 2022. "Proteogenomics refines the molecular classification of chronic lymphocytic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Gerard Llimos & Vincent Gardeux & Ute Koch & Judith F. Kribelbauer & Antonina Hafner & Daniel Alpern & Joern Pezoldt & Maria Litovchenko & Julie Russeil & Riccardo Dainese & Riccardo Moia & Abdurraouf, 2022. "A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Maurizio Mangolini & Alba Maiques-Diaz & Stella Charalampopoulou & Elena Gerhard-Hartmann & Johannes Bloehdorn & Andrew Moore & Giorgia Giachetti & Junyan Lu & Valar Nila Roamio Franklin & Chandra Sek, 2022. "Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    4. Kakushadze, Zura & Yu, Willie, 2016. "Factor models for cancer signatures," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 462(C), pages 527-559.
    5. Roberta Esposito & Andrés Lanzós & Tina Uroda & Sunandini Ramnarayanan & Isabel Büchi & Taisia Polidori & Hugo Guillen-Ramirez & Ante Mihaljevic & Bernard Mefi Merlin & Lia Mela & Eugenio Zoni & Lusin, 2023. "Tumour mutations in long noncoding RNAs enhance cell fitness," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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