ERP114144 PRJEB31573 ena-STUDY-HUBRECHT INSTITUTE, UTRECHT, THE NETHERLANDS-06-03-2019-11:53:02:356-156 Degree and site of chromosomal instability define its role in tumorigenesis Aneuploidy is observed in as much as 70-90% of human cancers, and is the result of erroneoussegregation of chromosomes during mitosis. Such chromosomal instability (CIN) can lead tofurther genome destabilization, and is associated with high intra-tumoral heterogeneity andimmune evasion. Despite being a hallmark of cancer, the role of CIN and aneuploidy in tumorformation is unclear. This is mainly due to conflicting results from various mammalian models ofCIN that are difficult to compare in terms of genetics, impacted tissues, and timing and degree ofCIN. We here present a novel conditional mouse model that enables reproducible, tissuespecificinduction of five distinct levels of CIN in mice, from very low to very high. We find that aparticular range of CIN can drive very early onset adenoma formation in the intestine. In ApcMin/+mice, moderate and high CIN cause remarkable increases in tumors of the distal colon, resemblinghuman disease. By contrast, while moderate CIN is also tumor promoting in the small intestine, highCIN is not. Our data thus show that the right range of CIN can be potently oncogenic and that tissuesdiffer in their response to CIN. Aneuploidy is observed in as much as 70-90% of human cancers, and is the result of erroneoussegregation of chromosomes during mitosis. Such chromosomal instability (CIN) can lead tofurther genome destabilization, and is associated with high intra-tumoral heterogeneity andimmune evasion. Despite being a hallmark of cancer, the role of CIN and aneuploidy in tumorformation is unclear. This is mainly due to conflicting results from various mammalian models ofCIN that are difficult to compare in terms of genetics, impacted tissues, and timing and degree ofCIN. We here present a novel conditional mouse model that enables reproducible, tissuespecificinduction of five distinct levels of CIN in mice, from very low to very high. We find that aparticular range of CIN can drive very early onset adenoma formation in the intestine. In ApcMin/+mice, moderate and high CIN cause remarkable increases in tumors of the distal colon, resemblinghuman disease. By contrast, while moderate CIN is also tumor promoting in the small intestine, highCIN is not. Our data thus show that the right range of CIN can be potently oncogenic and that tissuesdiffer in their response to CIN. ENA-FIRST-PUBLIC 2019-10-31 ENA-LAST-UPDATE 2019-03-11