Degree and site of chromosomal instability define its oncogenic potential

Most human cancers are aneuploid, due to a chromosomal instability (CIN) phenotype. Despite being a hallmark of cancer, however, it is unclear what the impact is of CIN on tumor formation. Using a novel conditional mouse model for diverse degrees of CIN, we find that a particular range is sufficient to drive early onset tumor formation in the intestine. In mice predisposed to intestinal cancer (ApcMin/+), moderate and high CIN cause remarkable increases in tumor burden of the distal colon, resembling human disease. By contrast, in the same mice, high CIN has no impact on tumor formation in the small intestine. Correspondingly, colonic crypts of high CIN mice at the time of tumor initiation more readily maintain aberrant proliferative cells than those of the small intestine. Our results thus show that at a narrow range, and depending on the particular tissue setting, CIN can be potently oncogenic.