Arm-level CNAs reveal hidden breast cancer drivers via CRISPR screens

Researchers developed the CRISPR-KOALA platform to perform high-throughput bidirectional gene screens on recurrent arm-level copy-number alterations in immunocompetent mouse models of basal-like breast cancer. Screening 3,752 genes, they identified 90 cancer driver genes across signaling pathways such as MAPK, HIPPO and WNT, showing that arm-level CNAs can selectively recruit diverse drivers and that manipulating these genes can bypass the requirement for aneuploidy in TP53-mutant BLBC. Notably, PLGRKT on chromosome 9p emerged as a potent oncogene linked to stress-resistant mitochondria and enhanced ROS detox, illustrating how specific drivers may shape tumor heterogeneity driven by aneuploidy.