TY - JOUR
T1 - Genomic landscape and chronological reconstruction of driver events in multiple myeloma
AU - Maura, Francesco
AU - Bolli, Niccoló
AU - Angelopoulos, Nicos
AU - Dawson, Kevin J.
AU - Leongamornlert, Daniel
AU - Martincorena, Inigo
AU - Mitchell, Thomas J.
AU - Fullam, Anthony
AU - Gonzalez, Santiago
AU - Szalat, Raphael
AU - Abascal, Federico
AU - Rodriguez-Martin, Bernardo
AU - Samur, Mehmet Kemal
AU - Glodzik, Dominik
AU - Roncador, Marco
AU - Fulciniti, Mariateresa
AU - Tai, Yu Tzu
AU - Minvielle, Stephane
AU - Magrangeas, Florence
AU - Moreau, Philippe
AU - Corradini, Paolo
AU - Anderson, Kenneth C.
AU - Tubio, Jose M.C.
AU - Wedge, David C.
AU - Gerstung, Moritz
AU - Avet-Loiseau, Hervé
AU - Munshi, Nikhil
AU - Campbell, Peter J.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-11680-1
DO - 10.1038/s41467-019-11680-1
M3 - Article
C2 - 31444325
AN - SCOPUS:85071338370
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3835
ER -