Anueploidy selects for the acquisition of driver genes in breast cancer

Chromosome instability is highly prevalent in cancer and drives large scale chromosomal imbalances, known as aneuploidies. How aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here, we established a CRISPR Knock Out and Activation Linked Assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immune-competent mouse models of cancer. We developed a compendium of the ten most frequent human chromosome arm-level alterations in basal-like breast cancer (BLBC), a disease type driven by large copy number alterations (CNAs). Using CRISPR-KOALA, we screened the mouse orthologs of all 3,752 genes on these arms and identified 90 cancer driver genes, the vast majority of which have hitherto unknown functions in cancer. These genes drive distinct signalling pathways including MAPK, Hippo and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes the need for CNAs in p53-mutant BLBC mouse models. Mechanistically, we uncover PLGRKT as a potent oncogene that lies on chromosome 9p and show that its tumor-promoting activity is associated with highly stress-resistant mitochondria and an increased capacity to detoxify reactive oxygen species. Together, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogeneous biological processes.