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.
Highlights
The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases
We combine a large cohort of serial MM samples analyzed by whole-genome sequencing (WGS) with a publicly available dataset to define driver events and how they group across patients, with implications for disease classification
Our shortlist of genes showed a 65% overlap with a recently published study from the Myeloma Genome Project (MGP) (Supplementary Data 3)13, with less frequently mutated genes accounting for the discordant calls
Summary
The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Cases without IGH translocations often have a distinctive pattern of hyperdiploidy affecting odd-numbered chromosomes, where the underlying target genes remain mysterious. These SVs and recurrent CNAs are considered early drivers, being detectable in premalignant stages of the disease. Drawn from a restricted set of possible events, differ in which subsequent cancer genes confer clonal advantage, leading to considerable substructures of cooperativity and mutual exclusivity among cancer genes These subtypes vary in chemosensitivity and survival, suggesting that patients share a common histological and clinical phenotype, the underlying biology is distinctly heterogeneous. We describe the temporal evolution of the disease in preclinical phases, highlighting the unexpected dynamism of genomic changes, often in the form of private, complex structural events
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