Chromosomal instability in cancer: sources, consequences and new therapeutic opportunities

Chromosomal instability (CIN) refers to a high rate of chromosome segregation errors during consecutive cell divisions and is a hallmark of cancers with aggressive behavior and poor prognosis. Cancer cells exhibiting CIN may acquire both numerical (N-CIN) and structural (S-CIN) chromosome alterations, namely by chromosome mis-segregation and DNA replication/repair defects, respectively. Importantly, these processes are tightly interconnected: mis-segregating chromosomes are prone to DNA damage, while DNA replication or repair defects can, in turn, promote chromosome mis-segregation. Consequently, CIN emerges as a consequence of these intertwined occurrences. CIN can confer survival advantages to cancer cells by enhancing their adaptation abilities, promoting intratumor heterogeneity, therapy resistance and acquisition of metastatic potential. In contrast, induction of CIN in healthy cells typically compromises cellular fitness and viability, triggering senescence and apoptosis. Therefore, cancer cells develop specific adaptation capabilities that allow them to tolerate CIN, often becoming dependent on specific CIN tolerance pathways. Elucidating the molecular circuits underlying CIN and clarifying the basis of its multifaceted roles in cancer will deepen our understanding of tumorigenesis and reveal therapeutically exploitable vulnerabilities in chromosomally unstable cancers. Here, we provide an integrated perspective on the principal sources of CIN, newly identified CIN-specific dependencies and vulnerabilities and how CIN impacts genome integrity. We discuss emerging evidence on the potential influence of CIN on tumor evolution or regression, including the CIN paradox. We further highlight how integrating this novel information with emerging diagnostic technologies that allow quantitative, qualitative and spatiotemporal characterization of CIN within tumors is reshaping our ability to define CIN at the single-tumor level, opening new avenues for targeted therapeutic strategies.