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Timing the initiation of multiple myeloma

Author

Listed:
  • Even H. Rustad

    (Memorial Sloan Kettering Cancer Center)

  • Venkata Yellapantula

    (Memorial Sloan Kettering Cancer Center)

  • Daniel Leongamornlert

    (Wellcome Sanger Institute)

  • Niccolò Bolli

    (University of Milan
    Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Guy Ledergor

    (University of California)

  • Ferran Nadeu

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Nicos Angelopoulos

    (Wellcome Sanger Institute)

  • Kevin J. Dawson

    (Wellcome Sanger Institute)

  • Thomas J. Mitchell

    (Wellcome Sanger Institute)

  • Robert J. Osborne

    (Wellcome Sanger Institute)

  • Bachisio Ziccheddu

    (University of Milan
    University of Turin)

  • Cristiana Carniti

    (Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Vittorio Montefusco

    (Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Paolo Corradini

    (University of Milan
    Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Kenneth C. Anderson

    (Harvard Medical School)

  • Philippe Moreau

    (CRCINA, SIRIC ILIAD, University Hospital of Nantes)

  • Elli Papaemmanuil

    (Center for Computational Oncology, Memorial Sloan Kettering Cancer Center)

  • Ludmil B. Alexandrov

    (University of California, La Jolla)

  • Xose S. Puente

    (Universitat de Barcelona
    Universidad de Oviedo)

  • Elias Campo

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Universitat de Barcelona)

  • Reiner Siebert

    (Ulm University and Ulm University Medical Center)

  • Herve Avet-Loiseau

    (IUC-Oncopole, and CRCT INSERM U1037)

  • Ola Landgren

    (Memorial Sloan Kettering Cancer Center)

  • Nikhil Munshi

    (Harvard Medical School
    Veterans Administration Boston Healthcare System)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Francesco Maura

    (Memorial Sloan Kettering Cancer Center
    Wellcome Sanger Institute)

Abstract

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2nd-3rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

Suggested Citation

  • Even H. Rustad & Venkata Yellapantula & Daniel Leongamornlert & Niccolò Bolli & Guy Ledergor & Ferran Nadeu & Nicos Angelopoulos & Kevin J. Dawson & Thomas J. Mitchell & Robert J. Osborne & Bachisio Z, 2020. "Timing the initiation of multiple myeloma," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15740-9
    DOI: 10.1038/s41467-020-15740-9
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