Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy-relevant energies down to stopping

W Friedland, E Schmitt, P Kundrát, M Dingfelder, G Baiocco, S Barbieri, A Ottolenghi, W Friedland, E Schmitt, P Kundrát, M Dingfelder, G Baiocco, S Barbieri, A Ottolenghi

Abstract

Track structures and resulting DNA damage in human cells have been simulated for hydrogen, helium, carbon, nitrogen, oxygen and neon ions with 0.25-256 MeV/u energy. The needed ion interaction cross sections have been scaled from those of hydrogen; Barkas scaling formula has been refined, extending its applicability down to about 10 keV/u, and validated against established stopping power data. Linear energy transfer (LET) has been scored from energy deposits in a cell nucleus; for very low-energy ions, it has been defined locally within thin slabs. The simulations show that protons and helium ions induce more DNA damage than heavier ions do at the same LET. With increasing LET, less DNA strand breaks are formed per unit dose, but due to their clustering the yields of double-strand breaks (DSB) increase, up to saturation around 300 keV/μm. Also individual DSB tend to cluster; DSB clusters peak around 500 keV/μm, while DSB multiplicities per cluster steadily increase with LET. Remarkably similar to patterns known from cell survival studies, LET-dependencies with pronounced maxima around 100-200 keV/μm occur on nanometre scale for sites that contain one or more DSB, and on micrometre scale for megabasepair-sized DNA fragments.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. Setup of irradiation simulations.
Figure 1. Setup of irradiation simulations.
A circular ion source (red) is located tangentially to the cell nucleus in a surrounding water shell. 5 particles per run start with a given initial energy from random positions on the source area in normal direction to it; arrows illustrate carbon ion tracks of 0.25 MeV/u initial energy (range ~6 μm). Determination of LET (Fig. 2a) is based on energy deposits including secondary electrons inside nuclear volume (orange arrows); energy deposited outside the nucleus (green parts of the arrows) is not considered. Local analysis of DNA damage by slow ions (Fig. 6) is based on DNA amount and particle stopping power (Fig. 2b) in 200-nm-slabs (thin black lines). Primary and secondary particles leaving the surrounding shell are no longer scored. Coloured structures of the cell nucleus refer to chromatin of different chromosomes.
Figure 2. LET in dependence on the…
Figure 2. LET in dependence on the initial particle energy and penetrated depth.
Panel a: LET calculated from energy deposited within the cell nucleus (symbols connected by solid lines to guide the eyes) and comparison to stopping powers from ICRU (dotted lines). Panel b: LET determined from energy deposited in 200 nm slabs perpendicular to particle transport direction (histograms) for ions with 0.5 MeV/u (thick lines) or 0.25 MeV/u initial energy (thin lines). Stopping power data from ICRU shown by symbols (0.5 MeV/u: filled squares, 0.25 MeV/u: empty squares).
Figure 3. Ion irradiation-induced DNA damage in…
Figure 3. Ion irradiation-induced DNA damage in dependence on LET.
In panel a–e, simulation results are shown by symbols connected by lines to guide the eyes; error bars in panel a–d denote two standard errors of the mean (~95% confidence intervals) of the performed simulations. Panel a: SB yields from direct effects (dashed lines), indirect effects (dash-dotted lines), and both effects (symbols and solid lines). Panel b: DSB yields, in which isolated ones as well as individual DSB in DSB clusters are scored. Panel c: Yields of DSB sites, which comprise isolated DSB and DSB clusters; a DSB cluster is scored as one DSB site. Panel d: Yields of DSB clusters; a cluster includes two or more DSB within not more than 25 bp distance. Panel e: Average multiplicity of DSB in a cluster. Panel f: DSB induction by 60Co γ-rays, He, B, N and Ne ions measured by the pulsed-field gel electrophoresis technique from DNA fragments sized between 5 kbp and 6 Mbp (symbols) and corresponding simulation results considering detectable DNA fragments (solid lines).
Figure 4. Ion irradiation-induced DNA damage in…
Figure 4. Ion irradiation-induced DNA damage in dependence on (Zeff/β)2.
Simulation results are shown by symbols connected by lines to guide the eyes; error bars denote two standard errors of the mean (~95% confidence intervals) of the performed simulations. Panel a: SSB, i.e. breaks in DSB are not included (symbols and solid lines), with prediction of MCDS (dashed line). Panel b: DSB yields (symbols and solid lines) with prediction of MCDS (dashed line). Panel c: Yields of DSB sites, which comprise isolated DSB and DSB clusters; a DSB cluster is scored as one DSB site. Panel d: Yields of DSB clusters; a cluster includes two or more DSB within not more than 25 bp distance.
Figure 5. Simulation results on the yields…
Figure 5. Simulation results on the yields of DNA fragments by single ion tracks.
Simulation results are shown by symbols, connected by lines to guide the eyes. Error bars denote two standard errors of the mean of the performed simulations. The fragment size intervals (panel a: 60–100 bp; panel b: 0.3–3 kbp; panel c: 10–100 kbp; panel d: 0.3–3 Mbp) correspond to fragments formed when an ion track induces a pair of DSB sites within a nucleosome, chromatin fiber, a chromatin fiber loop, and a chromatin domain (or a giant loop), respectively.
Figure 6. Simulated DNA damage induced in…
Figure 6. Simulated DNA damage induced in slabs of 200 nm thickness by ions with 0.25 MeV/u initial energy in dependence on the LET within that slab (Fig. 2b).
Symbols connected by solid lines to guide the eye refer to subsequent slabs; dotted lines show the total damage yields in dependence on the nucleus-averaged LET (presented in Fig. 3b–d). Panel a: SB yields from direct and indirect effects. Panel b: DSB yields, in which isolated ones as well as individual DSB in DSB clusters are scored. Panel c: Yields of DSB sites, which comprise isolated DSB and DSB clusters; a DSB cluster is scored as one DSB site. Panel d: Yields of DSB clusters; a cluster includes two or more DSB within not more than 25 bp distance. The LET and the yields of DNA damage in the first slab are indicated by arrows; when the ion slows down, the damage yields proceed along the solid lines.

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