Chromosomal Instability, Selection and Competition: Factors That Shape the Level of Karyotype Intra-Tumor Heterogeneity

SIMPLE SUMMARY: Each cancer consists of billions of cells. These cells are far from identical; hence, the population of cells that constitute a tumor is heterogeneous. A salient property that varies between cells in a tumor is their karyotype, the number and configuration of the chromosomes. The level of karyotype heterogeneity can be used to predict the survival of a patient. In this review, we describe the processes that shape the level of karyotype heterogeneity in a cancer. ABSTRACT: Intra-tumor heterogeneity (ITH) is a pan-cancer predictor of survival, with high ITH being correlated to a dismal prognosis. The level of ITH is, hence, a clinically relevant characteristic of a malignancy. ITH of karyotypes is driven by chromosomal instability (CIN). However, not all new karyotypes generated by CIN are viable or competitive, which limits the amount of ITH. Here, we review the cellular processes and ecological properties that determine karyotype ITH. We propose a framework to understand karyotype ITH, in which cells with new karyotypes emerge through CIN, are selected by cell intrinsic and cell extrinsic selective pressures, and propagate through a cancer in competition with other malignant cells. We further discuss how CIN modulates the cell phenotype and immune microenvironment, and the implications this has for the subsequent selection of karyotypes. Together, we aim to provide a comprehensive overview of the biological processes that shape the level of karyotype heterogeneity.