Timing the initiation of multiple myeloma

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 Ziccheddu, Cristiana Carniti, Vittorio Montefusco, Paolo Corradini, Kenneth C. Anderson, Philippe Moreau, Elli Papaemmanuil, Ludmil B. Alexandrov, Xose S. Puente, Elias Campo, Reiner Siebert, Herve Avet-Loiseau, Ola Landgren, Nikhil Munshi, Peter J. Campbell and Francesco Maura ()
Additional contact information
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
Guy Ledergor: University of California
Ferran Nadeu: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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
Cristiana Carniti: Fondazione IRCCS Istituto Nazionale dei Tumori
Vittorio Montefusco: Fondazione IRCCS Istituto Nazionale dei Tumori
Paolo Corradini: University of Milan
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
Elias Campo: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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
Peter J. Campbell: Wellcome Sanger Institute
Francesco Maura: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15740-9

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