The evolution and progression of multiple myeloma (MM) and its precursors over time is poorly understood. Here, we investigated the landscape and timing of mutational processes shaping MM evolution in a large cohort of 89 whole genomes and 973 exomes. Eight processes were identified, including a new mutational signature associated with exposure to alkylating agents. Reconstructing the chronological activity of each mutational signature, we estimated that initial transformation of a germinal center B-cell usually occurred during the first 2-3 decades of life. From there the transformed cells followed one of four main trajectories to MM, each reflecting a distinct order of mutational processes driving tumor evolution. Our findings provide a framework to study the etiology of MM and explore strategies for prevention and early detection.
Keywords: Multiple Myeloma, Mutational Signatures, Molecular Time, Cancer Initiation, Germinal Center
Rustad, Even H. and Yellapantula, Venkata and Bolli, Niccolo and Leongamornlert, Daniel and Nadeu, Ferran and Angelopoulos, Nicos and Dawson, Kevin J. and Mitchell, Thomas J. and Osborne, Rob and Ziccheddu, Bachisio and Cariniti, Cristiana and Montefusco, Vittorio and Corradini, Paolo and Anderson, Kenneth C. and Moreau, Philippe and Papaemmanuil, Elli and Alexandrov, Ludmil and Puente, Xose S. and Campo, Elias and Siebert, Reiner and Avet-Loiseau, Herve and Landgren, Ola and Munshi, Nikhil and Campbell, Peter J. and Maura, Francesco, Timing the Initiation of Multiple Myeloma (June 25, 2019). Available at SSRN: https://ssrn.com/abstract=3409453 or http://dx.doi.org/10.2139/ssrn.3409453
This version of the paper has not been formally peer reviewed.
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