Systematic analysis of genetic vulnerabilities caused by chromosome loss events in cancer

Loss of specific chromosomes in cancer cell lines creates 389 selectively associated CRISPR-screened genetic dependencies, with paralog insufficiency emerging as the most significant vulnerability mechanism.

• Why it matters: Chromosome loss is common in tumors but rare in normal tissue, suggesting it could yield cancer-specific therapeutic targets that are linked to defined genomic events.
• What they did: The study integrated genome-scale CRISPR screening with chromosome-level copy number profiles from 1,150 cancer cell lines to map dependencies tied to individual chromosome loss events, then experimentally validated PPP2CB/PPP2CA and DDX3Y/DDX3X.
• The result: Acute DDX3X degradation triggered apoptosis in vitro and tumor regressions in mice, and selective DDX3X dependency in loss-of-Y cells exceeds other published aneuploidy vulnerabilities and matches or exceeds most clinically validated biomarker-target relationships.