Chojnacka, M. | bioRxiv Science

bioRxiv2024

Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma

To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.

cancer biology↗

bioRxiv2023

Impact of rare structural variant events in newly diagnosed multiple myeloma

Whole genome sequencing (WGS) of newly diagnosed multiple myeloma patients (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e. hotspots) and causing recurrent copy number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs". More than half SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined. In this study, we utilize 752 WGS and 591 RNA-seq data from NDMM patients to determine the role of rare SVs in myeloma pathogenesis. 94% of patients harbored at least one rare SV event. Rare SVs showed an SV-class specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs. Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a driver role in myeloma pathogenesis. SIGNIFICANCECharacterization of multiple myeloma genome revealed that more than half structural variants are not involved in recurrent events. Here, we demonstrate that these rare SVs hold potential for myeloma pathogenesis through their gene expression impact. Rare SVs contribute to MM heterogeneity and have implications for development of individualized treatment.

cancer biology↗