Computational model of dose response for low-LET-induced complex chromosomal aberrations.

Experiments with full-colour mFISH chromosome painting have revealed high yield of radiation-induced complex chromosomal aberrations (CAs). The ratio of complex to simple aberrations is dependent on cell type and linear energy transfer. Theoretical analysis has demonstrated that the mechanism of CA formation as a result of interaction between lesions at a surface of chromosome territories does not explain high complexes-to-simples ratio in human lymphocytes. The possible origin of high yields of γ-induced complex CAs was investigated in the present work by computer simulation. CAs were studied on the basis of chromosome structure and dynamics modelling and the hypothesis of CA formation on nuclear centres. The spatial organisation of all chromosomes in a human interphase nucleus was predicted by simulation of mitosis-to-interphase chromosome structure transition. Two scenarios of CA formation were analysed, 'static' (existing in a nucleus prior to irradiation) centres and 'dynamic' (formed in response to irradiation) centres. The modelling results reveal that under certain conditions, both scenarios explain quantitatively the dose-response relationships for both simple and complex γ-induced interchromosomal exchanges observed by mFISH chromosome painting in the first post-irradiation mitosis in human lymphocytes.

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.

Complex interchanges as a complex function of chromosome organisation.

A Monte Carlo technique was developed for biophysical modelling of structural organisation of 46 chromosomes within human lymphocyte interphase nucleus. The technique takes into account: different levels of chromatin organisation, non-random localisation of particular chromosomes and chromosome loci dynamics. All chromosomes in a nucleus were modelled as polymer globules. A dynamic pattern of intra/interchromosomal contacts was simulated to predict radiation-induced chromosomal exchange aberrations (CA). Distance dependence of interaction probability was calculated directly with taking DNA break repair into account. Dose-response for simple and complex CA was calculated to analyse mFISH data for human lymphocytes. Calculated simple CA frequencies fitted the experimental data well. Unexpectedly, complex aberrations were underestimated, despite the dense packaging of chromosome territories within a nucleus. To study sensitivity of dose-response to uncertainty of chromosome organisation, CA were recalculated for the alternative concept of nucleus organisation, the SCD model. The simulation showed the underestimation of complex CA yield as well. The movement of damaged loci from different chromosomes to common repair factories was proposed as an additional mechanism of complex CA formation.

Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis.

Methodological problems arise on the way of radiation carcinogenesis modelling with the incorporation of radiobiological and cancer biology mechanistic data. The results of biophysical modelling of different endpoints [DNA DSB induction, repair, chromosome aberrations (CA) and cell proliferation] are presented and applied to the analysis of RBE-LET relationships for radiation-induced neoplastic transformation (RINT) of C3H/10T1/2 cells in culture. Predicted values for some endpoints correlate well with the data. It is concluded that slowly repaired DSB clusters, as well as some kind of CA, may be initiating events for RINT. As an alternative interpretation, it is possible that DNA damage can induce RINT indirectly via epigenetic process. A hypothetical epigenetic pathway for RINT is discussed.