Genomic landscape and chronological reconstruction of driver events in multiple myeloma
Kevin J. Dawson,
Thomas J. Mitchell,
Mehmet Kemal Samur,
Yu Tzu Tai,
Kenneth C. Anderson,
Jose M. C. Tubio,
David C Wedge,
Peter J. Campbell
Posted 12 Aug 2018
bioRxiv DOI: 10.1101/388611 (published DOI: 10.1038/s41467-019-11680-1)
Posted 12 Aug 2018
Multiple myeloma (MM) has a heterogeneous genome, evolving through both pre-clinical and post-diagnosis phases. Here, using sequences from 67 MM genomes serially collected from 30 patients together with public datasets, we establish a hierarchy of driver lesions. Point mutations, structural variants and copy number aberrations define at least 7 genomic subgroups of MM, each with distinct sets of co-operating driver mutations. Complex structural events are major drivers of MM, including chromothripsis, chromoplexy and a replication-based mechanism of templated insertions: these typically occur early. Hyperdiploidy also occurs early, with individual chromosomes often gained in more than one chronological epoch of MM evolution, showing a preferred order of acquisition. Positively selected point mutations frequently occur in later phases of disease development, as do structural variants involving MYC. Thus, initiating driver events of MM, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of subsequent evolution.
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