Maura, FrancescoBolli, NiccolóAngelopoulos, NicosDawson, Kevin J.Leongamornlert, DanielMartincorena, InigoMitchell, Thomas J.Fullam, AnthonyGonzález Rosado, SantiagoSzalat, RaphaelAbascal, FedericoRodríguez Martín, BernardoKemal Samur, MehmetGlodzik, DominikRoncador, MarcoFulciniti, MariateresaTai, Yu TzuMinvielle, StephaneMagrangeas, FlorenceMoreau, PhilippeCorradini, PaoloAnderson, Kenneth C.Castro Tubío, José ManuelWedge, David C.Gerstung, MoritzAvet-Loiseau, HervéMunshi, NikhilCampbell, Peter J.2020-04-282020-04-282019Maura, F., Bolli, N., Angelopoulos, N. et al. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun 10, 3835 (2019). https://doi.org/10.1038/s41467-019-11680-1http://hdl.handle.net/10347/21835The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients.eng© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/http://creativecommons.org/ licenses/by/4.0/Cancer genomicsMyelomajournal article10.1038/s41467-019-11680-12041-1723open access