Heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction

Abstract

AbstractThe incidence of somatic copy number alterations (SCNAs) per base pair of the genome is orders of magnitudes larger than that of point mutations. This makes SCNAs phenotypically effective. One mitotic event stands out in its potential to significantly change a cell’s SCNA burden – a chromosome missegregation. We present a general deterministic framework for modeling whole chromosome missegregations and use it to evaluate the possibility of missegregation-induced population extinction (MIE). The model predicts critical curves that separate viable from non-viable populations as a function of their turnover- and mis-segregation rates. Missegregation- and turnover rates estimated for nine cancer types are then compared to these predictions. The majority of tumors across all nine cancer types had missegregation- and turnover rates that were within viable regions of the parameter space. When a dependency of mis-segregation rate on ploidy was introduced, ploidy states associated with low mis-segregation rates acted as a stabilizing refuge, rendering MIE impossible when turnover rates are low. Intra-tumor heterogeneity, including heterogeneity in mis-segregation rates, increases as tumors progress. Our predictions suggest that this intra-tumor heterogeneity hampers the chance of success of therapies aimed at MIE.