Aneuploidy drives the acquisition of cancer-specific driver genes
Aneuploidy, the accumulation of numerical chromosome imbalances, is one of the most prevalent alterations in cancer genomes. However, how aneuploidy contributes to tumorigenesis is notoriously difficult to study due to the vast numbers of genes affected. Here, we develop CRISPR-KOALA (CRISPR-Knock Out and Activation Linked Assay), a high-throughput bidirectional screening method for simultaneous gene knockout and activation in immune-competent, sensitized mouse models of cancer. We use CRISPR-KOALA to screen the mouse orthologs of all 3,752 genes on the ten most frequently altered human chromosome arms in basal-like breast cancer (BLBC), a copy number-driven disease. We identify 90 cancer driver genes, the vast majority of which have hitherto unknown functions in cancer. These genes drive distinct transcriptional pathways including MAPK, Hippo and WNT, reflecting the high degree of heterogeneity associated with BLBC. Manipulating any of the identified cancer driver genes overcomes the need for aneuploidies inherent to BLBC and to our p53-mutant mouse models. Mechanistically, we uncover PLGRKT on chr9p as a potent oncogene directly adjacent to CD274. Its tumor-promoting activity is associated with a non-canonical function that involves the creation of highly stress-resistant mitochondria that promote tumor cell survival. Thus, our findings reveal that each arm-level copy number alteration is selected for by specific driver genes, rather than being a stochastic event caused by chromosomal instability, to drive heterogenous biological processes.