Tracing the evolution of trisomy in myeloid malignancies.

Chromosomal instability is a hallmark of cancer. While much is known about the genomic states that predispose to structural chromosomal instability, numerical chromosomal instability has remained its Cinderella sister for well over a century.

In this live webinar, Asif Javed will share how they combined bulk and single-cell DNA sequencing to investigate whole-chromosome gains, or trisomies, in myeloid malignancies. Bulk sequencing identified recurrent mutations in regulatory genes enriched in trisomy-positive patients. By profiling mutations and karyotype at the single-cell level, Mission Bio’s Tapestri platform, using a custom target panel, enabled reconstruction of clonal phylogenies and temporal ordering of these events. Taken together with analysis of data from a phenotypic CRISPR screen and evolutionary simulations, these findings support a model in which cumulative disruption of regulatory genes progressively destabilizes chromosome segregation, leading to whole-chromosome gain.

These findings demonstrate how single-cell profiling used in parallel with other molecular methods can provide a more complete view of how numerical chromosomal instability emerges and evolves in cancer. This approach may help uncover the mechanisms underlying chromosomal imbalance and provide new opportunities to understand its role in disease progression.