Genomic landscape and chronological reconstruction of driver events in multiple myeloma
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. ; F.M. is supported by AIL (Associazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS), by SIES (Società Italiana di Ematologia Sperimentale), and by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). N.B. is funded by AIRC (Associazione Italiana per la Ricerca sul Cancro) through a MFAG (no. 17658) and by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). This work was supported by Department of Veterans Affairs Merit Review Award I01BX001584-01 (N.C.M.), NIH grants P01-155258 (N.C.M., H.A.L., M.F., P.J.C. and K.C.A.) and 5P50CA100707-13 (N.C.M., H.A.L. and K.C.A) ; SI