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Timing the initiation of multiple myeloma

Even Rustad 1 Venkata Yellapantula 1 Daniel Leongamornlert 2 Niccolò Bolli 3, 4 Guy Ledergor 5 Ferran Nadeu 6, 7 Nicos Angelopoulos 2 Kevin Dawson 2 Thomas Mitchell 2 Robert Osborne 2 Bachisio Ziccheddu 3, 8 Cristiana Carniti 4 Vittorio Montefusco 4 Paolo Corradini 3, 4 Kenneth Anderson 9, 10 Philippe Moreau 11 Elli Papaemmanuil 1 Ludmil Alexandrov 12 Xose Puente 13, 14 Elias Campo 13, 6, 7 Reiner Siebert 15, 16 Herve Avet-Loiseau 17 Ola Landgren 1 Nikhil Munshi 9, 10, 18 Peter Campbell 2 Francesco Maura 2, 1
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 2 nd -3 rd 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.
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Submitted on : Wednesday, December 22, 2021 - 10:25:46 AM
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Even Rustad, Venkata Yellapantula, Daniel Leongamornlert, Niccolò Bolli, Guy Ledergor, et al.. Timing the initiation of multiple myeloma. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.1917. ⟨10.1038/s41467-020-15740-9⟩. ⟨inserm-03500314⟩



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