Abstract
Mathematical modelling has been instrumental to understand kinetics of radiation-induced DNA damage repair and associated secondary cancer risk. The widely accepted two-lesion kinetic (TLK) model assumes two kinds of double strand breaks, simple and complex ones, with different repair rates. Recently, persistent DNA damage associated with telomeres was reported as a new kind of DNA damage. We therefore extended existing versions of the TLK model by new categories of DNA damage and re-evaluated those models using extensive data. We subjected different versions of the TLK model to a rigorous model discrimination approach. This enabled us to robustly select a best approximating parsimonious model that can both recapitulate and predict transient and persistent DNA damage after ionizing radiation. Models and data argue for i) nonlinear dose-damage relationships, and ii) negligible saturation of repair kinetics even for high doses. Additionally, we show that simulated radiation-induced persistent telomere-associated DNA damage foci (TAF) can be used to predict excess relative risk (ERR) of developing secondary leukemia after fractionated radiotherapy. We suggest that TAF may serve as an additional measure to predict cancer risk after radiotherapy using high dose rates. This may improve predicting risk-dose dependency of ionizing radiation especially for long-term therapies.
Highlights
Mathematical models of DNA damage dynamics have been instrumental to understand mechanisms and kinetics of ionizing radiation (IR)-induced DNA damage repair for over 60 years[1,2,3,4]
The number of persistent telomere-associated DNA damage increases with increasing radiation dose[17,18]. Such persistent DNA damage is important for radiotherapy applications where accumulated doses are high. To incorporate these recent findings into existing models of DNA damage dynamics, we extended the two-lesion kinetic (TLK) model by additional categories of double strand breaks (DSBs), namely telomere-associated DNA damage foci (TAF) and basal background damage (B) and validated the extended DNA damage model with measured data (note that TAF is an acronym, whereas TAF refers to a model variable (Fig. 1))
Accounting for new insights about telomere-associated DNA damage repair outlined above, we extended this model with additional DSB categories, namely telomere-associated damage foci (TAF) and basal background damage (B) (Fig. 1)
Summary
Mathematical models of DNA damage dynamics have been instrumental to understand mechanisms and kinetics of ionizing radiation (IR)-induced DNA damage repair for over 60 years[1,2,3,4]. To describe the dynamics of the most severe type of DNA damage, i.e. double strand breaks (DSBs), the two-lesion kinetic (TLK) model is widely accepted[1,10] This model proposes two kinds of DSBs, simple and complex ones, which are repaired with different rates. It has been argued that some simple DSBs contain additional elementary damage sites (base damage, strand breaks, base deletion, etc.) within the same section of DNA, which renders them more complex, and longer, to repair[1] Both types of DSBs are principally repaired following a first-order kinetic. The parameters cannot directly be linked to molecular entities or processes
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