Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides
A partir d'échantillons tumoraux prélevés pendant une période de 5 ans sur un patient atteint d'un myélome multiple, cette étude de séquençage du génome entier met en évidence l'évolution des variants génomiques depuis le diagnostic jusqu'à la progression vers une leucémie secondaire
The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole genome sequencing (WGS) on four purified tumor samples and patient germline DNA drawn over a five year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single nucleotide variants (SNV) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors suggesting the presence of multiple independent, yet related clones at diagnosis that rose and fell in dominance. Five newly acquired SNV, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.
Blood 2012