Cancer: a CINful evolution.

Pioneering studies described cancer as an evolutionary process and detailed its intratumor heterogeneity in patients' specimens. The development of unbiased single-cell sequencing technologies confirmed these early observations and neoplasms are now widely recognized as populations of genetically, chromosomally and epigenetically distinct cells in which clones carrying beneficial traits expand in presence of selection factors like chemotherapy treatment. In support of this view, intratumor heterogeneity, by providing a large pool of phenotypically distinct clones, was shown to correlate with poor prognosis, therapy failure and metastasis. While most research has been focused on the role of nucleotide sequence variation, in recent years an increasing body of evidence suggests that aneuploidy and chromosome instability (CIN) contribute to tumor evolution. Here, we review recent advances in our understanding of the causes of aneuploidy and CIN and detail how they provide phenotypic variation at the cellular level. Moreover, we discuss evidences that aneuploidy and CIN kickstart a vicious loop generating genetic and karyotypic instability and provide clinical and experimental observations linking them to cancer progression. Finally, we suggest that aneuploidy and CIN contribute to tumor evolution by generating genome instability and intratumor heterogeneity.