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Mutations driving CLL and their evolution in progression and relapse

Author

Listed:
  • Dan A. Landau

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Brigham and Women’s Hospital
    Harvard Medical School)

  • Eugen Tausch

    (Ulm University)

  • Amaro N. Taylor-Weiner

    (Broad Institute of Harvard and MIT)

  • Chip Stewart

    (Broad Institute of Harvard and MIT)

  • Johannes G. Reiter

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    IST Austria (Institute of Science and Technology Austria)
    Program for Evolutionary Dynamics, Harvard University)

  • Jasmin Bahlo

    (University Hospital)

  • Sandra Kluth

    (University Hospital)

  • Ivana Bozic

    (Program for Evolutionary Dynamics, Harvard University
    Harvard University)

  • Mike Lawrence

    (Broad Institute of Harvard and MIT)

  • Sebastian Böttcher

    (University Hospital of Schleswig-Holstein, Campus Kiel)

  • Scott L. Carter

    (Broad Institute of Harvard and MIT
    Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School)

  • Kristian Cibulskis

    (Broad Institute of Harvard and MIT)

  • Daniel Mertens

    (Ulm University
    Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ))

  • Carrie L. Sougnez

    (Broad Institute of Harvard and MIT)

  • Mara Rosenberg

    (Broad Institute of Harvard and MIT)

  • Julian M. Hess

    (Broad Institute of Harvard and MIT)

  • Jennifer Edelmann

    (Ulm University)

  • Sabrina Kless

    (Ulm University)

  • Michael Kneba

    (University Hospital of Schleswig-Holstein, Campus Kiel)

  • Matthias Ritgen

    (University Hospital of Schleswig-Holstein, Campus Kiel)

  • Anna Fink

    (University Hospital)

  • Kirsten Fischer

    (University Hospital)

  • Stacey Gabriel

    (Broad Institute of Harvard and MIT)

  • Eric S. Lander

    (Broad Institute of Harvard and MIT)

  • Martin A. Nowak

    (Program for Evolutionary Dynamics, Harvard University
    Harvard University
    Harvard University)

  • Hartmut Döhner

    (Ulm University)

  • Michael Hallek

    (University Hospital
    Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD))

  • Donna Neuberg

    (Biostatistics and Computational Biology, Dana-Farber Cancer Institute)

  • Gad Getz

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • Stephan Stilgenbauer

    (Ulm University)

  • Catherine J. Wu

    (Broad Institute of Harvard and MIT
    Dana-Farber Cancer Institute
    Brigham and Women’s Hospital
    Harvard Medical School)

Abstract

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

Suggested Citation

  • Dan A. Landau & Eugen Tausch & Amaro N. Taylor-Weiner & Chip Stewart & Johannes G. Reiter & Jasmin Bahlo & Sandra Kluth & Ivana Bozic & Mike Lawrence & Sebastian Böttcher & Scott L. Carter & Kristian , 2015. "Mutations driving CLL and their evolution in progression and relapse," Nature, Nature, vol. 526(7574), pages 525-530, October.
    • Handle: RePEc:nat:nature:v:526:y:2015:i:7574:d:10.1038_nature15395
    DOI: 10.1038/nature15395
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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. 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.
    3. Janek S. Walker & Zachary A. Hing & Steven Sher & James Cronin & Katie Williams & Bonnie Harrington & Jordan N. Skinner & Casey B. Cempre & Charles T. Gregory & Alexander Pan & Max Yano & Larry P. Bea, 2021. "Rare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Othman Al-Sawaf & Can Zhang & Hyun Yong Jin & Sandra Robrecht & Yoonha Choi & Sandhya Balasubramanian & Alex Kotak & Yi Meng Chang & Anna Maria Fink & Eugen Tausch & Christof Schneider & Matthias Ritg, 2023. "Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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