Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

Abstract

Most tumors have abnormal karyotypes, which arise from mistakes during mitotic division of healthy euploid cells and evolve through numerous complex mechanisms. In a recent mouse model with high levels of chromosome missegregation, chromosome gains dominate over losses both in pretumor and tumor tissues, whereas tumors are characterized by gains of chromosomes 14 and 15. However, the mechanisms driving clonal selection leading to tumor karyotype evolution remain unclear. Here we show, by introducing a mathematical model based on a concept of a macro-karyotype, that tumor karyotypes can be explained by proliferation-driven evolution of aneuploid cells. In pretumor cells, increased apoptosis and slower proliferation of cells with monosomies lead to predominant chromosome gains over losses. Tumor karyotypes with gain of one chromosome can be explained by karyotype-dependent proliferation, while for those with two chromosomes an interplay with karyotype-dependent apoptosis is an additional possible pathway. Thus, evolution of tumor-specific karyotypes requires proliferative advantage of specific aneuploid karyotypes. SignificanceMost tumors have an erroneous number of chromosomes, which arise from mistakes during division of healthy cells and evolve through numerous complex mechanisms, including chromosome missegregation, cell proliferation and cell death. However, understanding the mechanisms leading to tumor evolution from healthy cells is a hot topic. Here we show, by introducing a "macro-karyotype model", that perturbed number of chromosomes in tumor cells arises predominantly from faster division of cells characterized by a specific combination of chromosomes, or together with irregular cell death. This finding, strengthened by comparison of our theory with experimentally observed combination of chromosomes in different stages of tumor development, gives a direction for future experiments in identifying the key processes underlying tumor development.