Quantifying chromosomal instability from intratumoral karyotype diversity using agent-based modeling and Bayesian inference

Abstract

Chromosomal instability (CIN)-persistent chromosome gain or loss through abnormal mitotic segregation-is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rate, a measure of CIN, can inform prognosis and is a promising biomarker for response to anti-microtubule agents. However, existing methodologies to measure this rate are labor intensive, indirect, and confounded by selection against aneuploid cells, which reduces observable diversity. We developed a framework to measure CIN, accounting for karyotype selection, using simulations with various levels of CIN and models of selection. To identify the model parameters that best fit karyotype data from single-cell sequencing, we used approximate Bayesian computation to infer mis-segregation rates and karyotype selection. Experimental validation confirmed the extensive chromosome mis-segregation rates caused by the chemotherapy paclitaxel (18.5±0.5/division). Extending this approach to clinical samples revealed that inferred rates fell within direct observations of cancer cell lines. This work provides the necessary framework to quantify CIN in human tumors and develop it as a predictive biomarker.

Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer

“…CIN+ cancer cell lines exhibit low rates of CIN (1–9 × 10 −3 missegregations per chromosome), as measured by mitotic defects, which serve as a validated proxy for CIN ( 11, 12 ). Mathematical modeling confirms that this low CIN rate optimizes tumor suppressor loss and cellular heterogeneity while maintaining viability ( 1, 3, 13 ), likely because low CIN allows tumors to opportunistically select from a variety of karyotypes to increase fitness ( 14–18 ). Aneuploidy and CIN are associated with metastasis and poor prognosis in certain tumor types ( 19, 20 ); subdividing tumors based on rates of CIN reveals that high CIN tumors result in improved outcomes relative to those with lower rates ( 21–25 ).…”

“…Chromosomal instability (CIN), the rate of persistent mitotic defects over consecutive divisions, results in random aneuploidy in daughter cells that is further shaped by selection ( 1, 2 ). Rates of CIN can vary widely from a single missegregated chromosome every few divisions to >10 chromosomes missegregated in a single division ( 3 ).…”

Intra-tumor heterogeneity, turnover rate and karyotype space shape susceptibility to missegregation-induced extinction

“…on the tumor microenvironment) renders reconstruction of fitness landscapes a challenging task. Nevertheless, recent efforts have linked specific karyotypes to differences in cell fitness [73], albeit under several simplifying, and partly unrealistic assumptions (e.g. neglecting epistasis).…”

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

“…While in healthy cells, aneuploidy causes a strong anti-proliferative response as a result of gene dosage imbalances (Santaguida et al, 2015) this response can be overcome in cancer cells, allowing the increased frequency of errors to promote aneuploid karyotype evolution and acceleration of tumor formation (Duijf & Benezra, 2013; van Jaarsveld & Kops, 2016). These ideas have emerged from extensive studies of aneuploidy in different systems including cell lines (Cimini et al, 2001; Thompson & Compton, 2008, 2011a), organoids (Bolhaqueiro et al, 2019; Drost & Clevers, 2018; Narkar et al, 2021), animal models (Bolton et al, 2016; Sheppard et al, 2012; Shoshani et al, 2021; Trakala et al, 2021), as well as theoretically (Araujo et al, 2013; Desper et al, 2005; Elizalde et al, 2018; Gusev et al, 2000, 2001; Laughney et al, 2015; Lynch et al, 2021). Yet, how the interplay between chromosome missegregation, cell proliferation and other processes drives long-term karyotype evolution is poorly understood.…”

“…A study of karyotype evolution that includes the interplay between missegregation and whole genome duplication found that population converges to near triploid state (Laughney et al, 2015), and that heterogeneity is primary influenced by the missegregation rate (Elizalde et al, 2018). Recently, a theoretical model was developed to measure CIN from karyotype diversity within a tumor (Lynch et al, 2022).…”