Modelling the HPRT-gene mutation induction of particle beams: systematic in vitro data collection, analysis and microdosimetric kinetic model implementation

Abstract

Objective. Since the early years, particle therapy treatments have been associated with concerns for late toxicities, especially secondary cancer risk (SCR). Nowadays, this concern is related to patients for whom long-term survival is expected (e.g. breast cancer, lymphoma, paediatrics). In the aim to contribute to this research, we present a dedicated statistical and modelling analysis aiming at improving our understanding of the RBE for mutation induction (RBEM˜) for different particle species.Approach. We built a new database based on a systematic collection of RBE data for mutation assays of the gene encoding for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase from literature (105 entries, distributed among 3 cell lines and 16 particle species). The data were employed to perform statistical and modelling analysis. For the latter, we adapted the microdosimetric kinetic model (MKM) to describe the mutagenesis in analogy to lethal lesion induction.Main results. Correlation analysis between RBE for survival (RBE_S) andRBEM˜reveals significant correlation between these two quantities (ρ= 0.86,p< 0.05). The correlation gets stronger when looking at subsets of data based on cell line and particle species. We also show that the MKM can be successfully employed to describeRBEM˜,obtaining comparably good agreement with the experimental data. Remarkably, to improve the agreement with experimental data the MKM requires, consistently in all the analysed cases, a reduced domain size for the description of mutation induction compared to that adopted for survival.Significance. We were able to show that RBE_SandRBEM˜are strongly related quantities. We also showed for the first time that the MKM could be successfully applied to the description of mutation induction, representing an endpoint different from the more traditional cell killing. In analogy to the RBE_S,RBEM˜can be implemented into treatment planning system evaluations.

Keywords: biophysical models; database; microdosimetric kinetic model (MKM); mutation induction; particle therapy; relative biological effectiveness (RBE).