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Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Maura, Francesco and Bolli, Niccoló and Angelopoulos, Nicos and Dawson, Kevin J and Leongamornlert, Daniel and Martincorena, Inigo and Mitchell, Thomas J and Fullam, Anthony and Gonzalez, Santiago and Szalat, Raphael and Abascal, Federico and Rodriguez-Martin, Bernardo and Samur, Mehmet Kemal and Glodzik, Dominik and Roncador, Marco and Fulciniti, Mariateresa and Tai, Yu Tzu and Minvielle, Stephane and Magrangeas, Florence and Moreau, Philippe and Corradini, Paolo and Anderson, Kenneth C and Tubio, Jose MC and Wedge, David C and Gerstung, Moritz and Avet-Loiseau, Hervé and Munshi, Nikhil and Campbell, Peter J (2019) 'Genomic landscape and chronological reconstruction of driver events in multiple myeloma.' Nature Communications, 10 (1). ISSN 2041-1723

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Abstract

The 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.

Item Type: Article
Divisions: Faculty of Science and Health > Computer Science and Electronic Engineering, School of
Depositing User: Elements
Date Deposited: 25 Sep 2019 15:49
Last Modified: 25 Sep 2019 15:49
URI: http://repository.essex.ac.uk/id/eprint/25335

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