Degree and site of chromosomal instability define its oncogenic potential

Abstract

Most human cancers are aneuploid, due to a chromosomal instability (CIN) phenotype. Despite being hallmarks of cancer, however, the roles of CIN and aneuploidy in tumor formation have not unequivocally emerged from animal studies and are thus still unclear. CIN can both promote and suppress tumorigenesis, but variances in mechanisms and timings of CIN induction in different oncogenic backgrounds and associated tissues limit interpretation of the contributions of CIN. Using a novel conditional mouse model for diverse degrees of CIN, we find that a particular range is sufficient to drive very early onset spontaneous adenoma formation in the intestine, showing that CIN can act as a much more potent oncogenic driver than was previously reported. In mice predisposed to intestinal cancer (Apc Min/+ ), moderate but not low CIN causes a remarkable increase in adenoma burden in the entire intestinal tract, especially in the distal colon, more closely modelling human disease. Strikingly, high levels of CIN promote adenoma formation in the distal colon even more than moderate CIN does, but have no effect in the small intestine. Our results thus show that CIN can be potently oncogenic, but that certain levels of CIN can have contrasting effects in distinct tissues. KEYWORDSChromosomal instability (CIN), aneuploidy, intestinal cancer, colorectal cancer (CRC), organoids, APC

Life or Death after a Break: What Determines the Choice?

“…Mitotic progression in the presence of DSBs causes chromosome instability (Harding et al, 2017;Leimbacher et al, 2019;van den Berg et al, 2018) and can produce segmental aneuploidy (Soto et al, 2019). The finding that mild chromosome instability is oncogenic highlights the hazard associated with DSBs traversing mitosis (Hoevenaar et al, 2019). Such segmental aneuploidies may be eliminated through p53-dependent mechanisms or due to the toxic effects of unbalanced karyotypes (Soto et al, 2017(Soto et al, , 2019.…”