Geant4-DNA simulation of DNA damage caused by direct and indirect radiation effects and comparison with biological data.

Villagrasa, C.; Meylan, Sylvain; Gonon, Géraldine; Gruel, Gaëtan; Giesen, U.; Bueno, M.; Rabus, Hans

doi:10.1051/epjconf/201715304019

Cited by 25 publications

(17 citation statements)

References 9 publications

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“…It should be noted that the scoring method for DNA damage can strongly influence the final yield of simulated DSB induction. As mentioned in our previous works [35,46,47], a change in the parameters to score direct and/or indirect strand breaks can greatly increase the yield of DSB. Moreover, a chemical simulation end-time of 10 ns has been suggested in our computation chain instead of the 2.5 ns currently used when considering the cell nucleus model filled with heterochromatin and euchromatin [46].…”

Section: Discussionmentioning

confidence: 90%

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations

Tang

Bueno

Meylan³

et al. 2019

IJMS

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The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

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Section: Discussionmentioning

confidence: 90%

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations

Tang

Bueno

Meylan³

et al. 2019

IJMS

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“…Instead, the assumptions that have been made, 10 bp damage separation and damage determined by an energy range probability, can only be described as conditions that produce reasonable results when compared to experiment. For example, recent work from Villagrasa et al 70 showed that using an energy threshold as the mechanism for direct strand break reproduces the experimental yield of 53BP1 foci. The impact of such parameters used for predicting DNA damage for electrons was recently presented by Lampe et al 71 Since the mechanism may not have been identi-ed, applying these conditions to a larger, more complex, system requires caution.…”

Section: Discussionmentioning

confidence: 95%

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons

et al. 2019

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“…Finally, it should also be noted that the yield of DNA DSBs can vary depending on the method used to score DNA damage. To illustrate this point, it was shown in previous study that the criterion used to determine direct damage can strongly influence the final DSB yields, even if the proportion of direct damage is lower than the proportion of indirect damage. In our simulation chain, the best fit to the experimental data was obtained using a threshold value of 17.5 eV instead of a linear probability from 5 to 37.5 eV .…”

Section: Discussionmentioning

confidence: 99%

Influence of chromatin compaction on simulated early radiation‐induced DNA damage using Geant4‐DNA

Tang

Bueno

Meylan³

et al. 2019

Medical Physics

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Purpose In this work, we present simulated double‐strand breaks (DSBs) obtained for two human cell nucleus geometries. The first cell nucleus represents fibroblasts, filled with DNA molecules in different compaction forms: heterochromatin or euchromatin only. The second one represents an endothelial cell nucleus, either filled with heterochromatin only or with a uniform distribution of 48% of heterochromatin and 52% of euchromatin, obtained from measurements carried out at IRSN. Protons and alpha particles of different energies were used as projectiles. Each cell nucleus model includes a multi‐scale description of the DNA target from the molecular level to the whole human genome representation. Methods The cell nucleus models were generated using an extended version of the DnaFabric software in which a new model of euchromatin was implemented in addition to the existing model of heterochromatin. Thus, each nucleus model contains the complete human genome (a total of 6 Gbp) in the G0/G1 phase of the cycle, filled with a continuous chromatin fiber per chromosome that can take into account the heterochromatin and the euchromatin compaction. These geometries were then exported to a simulation chain using the Monte Carlo toolkit Geant4‐DNA to perform computations of the physical, physicochemical, and chemical stages, in order to evaluate the influence of chromatin compaction on DSB induction and the contribution of direct and indirect damage, as well as DSB complexity. Results More direct damage and less indirect damage were observed in the heterochromatin than in the euchromatin. Nevertheless, no difference in terms of DSB complexity was observed between those formed in the heterochromatin or the euchromatin models. Yields of DSB/Gy/Gbp show an increase when both heterochromatin and euchromatin models are taken into account, compared to when only heterochromatin is considered. Conclusions The results presented indicate that the chromatin compaction decreases DNA damage generated by ionizing radiation and thus, DNA compaction should be considered for the simulation of DNA repair and other cellular outcomes.

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Geant4-DNA simulation of DNA damage caused by direct and indirect radiation effects and comparison with biological data.

Cited by 25 publications

References 9 publications

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons

Influence of chromatin compaction on simulated early radiation‐induced DNA damage using Geant4‐DNA

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