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 karyokinesis — is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rates, a measure of CIN, can inform prognosis and are a likely biomarker for response to anti-microtubule agents. However, existing methodologies to measure this rate are labor intensive, indirect, and confounded by karyotype selection reducing observable diversity. We developed a framework to simulate and measure CIN, accounting for karyotype selection, and recapitulated karyotype-level clonality in simulated populations. We leveraged approximate Bayesian computation using phylogenetic topology and diversity to infer mis-segregation rates and karyotype selection from single-cell DNA sequencing data. Experimental validation of this approach revealed extensive chromosome mis-segregation rates caused by the chemotherapy paclitaxel (17.5±0.14/division). Extending this approach to clinical samples revealed the 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.

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, 2000Gusev et al, , 2001Laughney 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).…”