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Timing the initiation of multiple myeloma

Rustad, Even H., Yellapantula, Venkata, Leongamornlert, Daniel, Bolli, Niccolo, Ledergor, Guy, Nadeu, Ferran, Angelopoulos, Nicos, Dawson, Kevin J., Mitchell, Thomas J., Osborne, Robert J., Ziccheddu, Bachisio, Carniti, Cristiana, Montefusco, Vittorio, Corradini, Paolo, Anderson, Kenneth C., Moreau, Philippe, Papaemmanuil, Elli, Alexandrov, Ludmil B., Puente, Xose S., Campo, Elias, Siebert, Reiner, Avet-Loiseau, Herve, Landgren, Ola, Munshi, Nikhil, Campbell, Peter J. and Maura, Francesco 2020. Timing the initiation of multiple myeloma. Nature Communications 11 (1) , 1917. 10.1038/s41467-020-15740-9

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License.
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 29 July 2020
Date of Acceptance: 26 March 2020
Last Modified: 18 Jan 2021 10:00
URI: http://orca.cf.ac.uk/id/eprint/133794

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