Tracing the evolution of trisomy in myeloid malignancies.

Chromosomal instability is a hallmark of cancer, but in myeloid malignancies it is still unclear which mutations come first and how whole-chromosome gains arise. In this webinar, Asif Javed of Chulabhorn Research Institute presents work using single-cell DNA sequencing on the Tapestri® platform to reconstruct the clonal history of trisomy in AML.

The team built a custom 181-amplicon panel. It covers 82 leukemia hotspots, with 99 more amplicons spread across chromosomes 4, 8, 11, 13 and 21, and they used it to profile 16 trisomy AML patients. They developed chromosome-specific models to infer trisomy in individual cells and found trisomy-positive cells in 14 of the 16 patients. In all 14, at least one mutation in a transcriptional or epigenetic regulator appeared before the chromosomal gain or on the same branch. In silico modeling with CINner supported a model in which these mutations gradually raise the risk of chromosome missegregation.

Key topics:

• Why ASXL1 truncation and its co-mutations point toward chromosome segregation defects
• Designing a targeted single-cell panel for high-confidence trisomy inference
• Calling trisomy and reconstructing phylogenies when amplicon performance varies
• Which regulatory mutations come before trisomy, and what they have in common
• Modeling the road to chromosomal instability