Quantifying high-LET heavy-ion-induced non-DSB clustered DNA lesions using Geant4-DNA

Ionizing radiation induces complex DNA damage that can challenge repair processes and contribute to genomic instability. In this study, we extend Geant4-DNA to quantify oxidative non-DSB damage containing 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) and thymidine glycol (dTg) from direct and hydroxyl-radical pathways. Simulations were performed in a reduced-scale human fibroblast chromatin geometry for 12 C, 28 Si, 40 Ar, and 56 Fe ions (LET 13–148 keV/μm). For 12 C irradiation at 94.55 MeV/u, including direct and quasi-direct oxidation raised the simulated 8-oxo-dG yield from 0.0059 ± 0.0002 to 0.0239 ± 0.0005 lesions/Mbp/Gy, approaching published experimental values. Simulated lesion frequencies matched experimental orders of magnitude, although discrepancies remained and the experimental assays and biological conditions were not fully equivalent to the simulated observables. The resulting damage profiles resolved lesion identity and local multiplicity. Clusters containing one single-strand break and one oxidative base lesion were the predominant non-DSB clustered configurations, particularly SSB + 8-oxo-dG (9.4%–13.2%) and SSB + dTg (8.5%–12.8%). This framework extends Geant4-DNA beyond conventional strand-break analysis, offering lesion-resolved inputs for mechanistic base excision repair models under heavy-ion irradiation.