Abstract A022: Decoding aneuploidy: Identifying drivers and therapeutic targets in recurrent breast cancer copy number alterations

Abstract Chromosome instability is highly prevalent in cancer and drives large scale chromosomal imbalances, known as aneuploidies. However, how aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. To address these limitations, we have developed a CRISPR-Knock Out and Activation Linked Assay (CRISPR-KOALA), which enables systematic high-throughput bidirectional genetic screens in immune-competent mouse models of cancer. Using CRISPR-KOALA we screened the mouse orthologs of all 3,752 genes residing on the ten most frequently altered human chromosome arms in basal-like breast cancer (BLBC), which to date is the largest bidirectional screen performed in vivo. Our screen identified 90 cancer driver genes, the vast majority of which have hitherto unknown functions in cancer. These genes drive distinct signalling pathways, reflecting the high degree of BLBC heterogeneity. Individual manipulation of the identified cancer driver genes completely overcomes the need for copy number alterations (CNAs) in p53-mutant BLBC mouse models. Mechanistically, we uncover PLGRKT as a potent oncogene and show that its tumor-promoting activity is associated with the creation of highly stress-resistant mitochondria that promote tumor cell survival, rather than through its canonical role of regulating the extracellular matrix. Overall, our work reveals that arm-level CNAs can function to select specific driver genes to promote heterogenous biological processes. Citation Format: Khalid N Al-Zahrani, Ellen R Langille, Andreea Obersterescu, Christopher Lowden, Katie Teng, Lauren Caldwell, David Cook, Miguel Pérez-Castro, Cynthia Chiu, Alexander Bahcheli2, Ricky Tsai, Jacob Berman, Kin Chan, Linkang Zhang, K.W. Annie Bang, Michael Parsons, Adele Lopes, Jocelyn Nurtanto, E. Idil Temel, Iosifina Fotiadou, Julien Dessapt, Hartland Jackson, Sean Egan, Jüri Reimand, Jeffrey Wrana, Daniel Schramek. Decoding aneuploidy: Identifying drivers and therapeutic targets in recurrent breast cancer copy number alterations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A022.