Dose-response prediction for radiation-induced chromosomal instability

Radiation induces chromosome aberrations (CA) that are detected in the first post-irradiation cell cycle and in descendants of irradiated cells. Unstable aberrations in the progeny of exposed cells are referred to as one of the hallmarks of chromosomal instability (CIN). One of the important questions is what is the relationship between the dose response for radiation-induced CA and delayed CA, or CIN. To address this question, a mechanistic model for CIN was developed. Delayed CA are assumed to be formed both by transmission from previous mitotic cycles owing to chromosome breakage-fusion mechanism and by means of generation of DNA/chromosome breakage de novo in each cell cycle of survived cells. Monte Carlo simulation of DNA/chromosome breakage, CA production, cell death due to unstable CA and cell cycle kinetics was performed to predict the dose response for CIN. Different shapes of CIN dose-response curves were predicted for various time points after irradiation and under several assumptions on delayed DNA/chromosome breakage generation. For one of the scenarios studied, the pronounced dose dependence at early time points flattened or even turned into dose independence in a wide dose range after many rounds of replication where a stationary state between CA generation and elimination was achieved. This dose independence was shown to be in concert with the experimental data.