Aneuploidy drives the acquisition of cancer-specific driver genes

Aneuploidy drives the acquisition of cancer-specific driver genes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Aneuploidy drives the acquisition of cancer-specific driver genes Daniel Schramek, Khalid Al-Zahrani, Ellen Langille, Andreea Obersterescu, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4941895/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version 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. Here, we develop 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 frequently altered human chromosome arms in basal-like breast cancer (BLBC), a copy number-driven disease. 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 copy number alterations (CNAs) in p53-mutant BLBC mouse models. Mechanistically, we uncover PLGRKT as a potent oncogene that lies adjacent to the immune checkpoint gene CD274/PD-L1 on chr9p and show that its tumor-promoting activity is associated with the creation of highly stress-resistant mitochondria that promote tumor cell survival. Thus, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogenous biological processes. Biological sciences/Cancer/Cancer genetics Biological sciences/Genetics/Functional genomics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1.Listofbasallikebreastcancercopynumberalterationhumangenesandmouseorthologs.xlsx Supplementary Table 1 SupplementaryTable2.ListofgRNAstargetingthemousehomologsofhumanbasallikebreastcancercopynumberalterations.xlsx Supplementary Table 2 SupplementaryTable3.SummaryofbasallikebreastcancercopynumberalterationCRISPRKOALAscreenhits.xlsx Supplementary Table 3 SupplementaryTable4.ListofdifferentiallyexpressedgenesinCNAcancergenetumors.xlsx Supplementary Table 4 SupplementaryTable5.ListofsignificantlyenrichedgeneontologytermsinCNAcancergenetumors.xlsx Supplementary Table 5 SupplementaryTable6.ListofsignificantlyenrichedpathwaysinbasallikebreastcancerpatientsstratifiedbyCNAcancergeneexpression.xlsx Supplementary Table 6 SupplementaryTable7.ListofprimersandvalidationgRNAs.xlsx Supplementary Table 7 SupplementaryTable8.ListofmarkersusedforCellAssign.xlsx Supplementary Table 8 SupplementaryTable9.ListofgeneIDsforhumantomousegeneconversions.xlsx Supplementary Table 9 SupplementaryTable10.Listofantibodies.xlsx Supplementary Table 10 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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