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Article

Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis

1
Laboratory of Health Physics, Radiobiology & Cytogenetics, Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientific Research “Demokritos”, 15341 Athens, Greece
2
DNA Damage Laboratory, Physics Department, School of Mathematical and Physical Sciences, National Technical University of Athens, 15780 Zografou, Greece
3
Legnaro National Laboratories, Italian Institute of Nuclear Physics, 35020 Legnaro (Padova), Italy
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(9), 2336; https://doi.org/10.3390/cancers12092336
Received: 1 July 2020 / Revised: 8 August 2020 / Accepted: 15 August 2020 / Published: 19 August 2020
For precision cancer radiotherapy, high linear energy transfer (LET) particle irradiation offers a substantial advantage over photon-based irradiation. In contrast to the sparse deposition of low-density energy by χ- or γ-rays, particle irradiation causes focal DNA damage through high-density energy deposition along the particle tracks. This is characterized by the formation of multiple damage sites, comprising localized clustered patterns of DNA single- and double-strand breaks as well as base damage. These clustered DNA lesions are key determinants of the enhanced relative biological effectiveness (RBE) of energetic nuclei. However, the search for a fingerprint of particle exposure remains open, while the mechanisms underlying the induction of chromothripsis-like chromosomal rearrangements by high-LET radiation (resembling chromothripsis in tumors) await to be elucidated. In this work, we investigate the transformation of clustered DNA lesions into chromosome fragmentation, as indicated by the induction and post-irradiation repair of chromosomal damage under the dynamics of premature chromosome condensation in G0 human lymphocytes. Specifically, this study provides, for the first time, experimental evidence that particle irradiation induces localized shattering of targeted chromosome domains. Yields of chromosome fragments and shattered domains are compared with those generated by γ-rays; and the RBE values obtained are up to 28.6 for α-particles (92 keV/μm), 10.5 for C-ions (295 keV/μm), and 4.9 for protons (28.5 keV/μm). Furthermore, we test the hypothesis that particle radiation-induced persistent clustered DNA lesions and chromatin decompaction at damage sites evolve into localized chromosome shattering by subsequent chromatin condensation in a single catastrophic event—posing a critical risk for random rejoining, chromothripsis, and carcinogenesis. Consistent with this hypothesis, our results highlight the potential use of shattered chromosome domains as a fingerprint of high-LET exposure, while conforming to the new model we propose for the mechanistic origin of chromothripsis-like rearrangements. View Full-Text
Keywords: high-LET particle radiation; protons; α-particles; C-ions; premature chromosome condensation (PCC); PCC assay; chromatin dynamics; chromothripsis; localized chromosome shattering; chromothripsis-like chromosomal rearrangements; RBE values; fingerprint of exposure; radiation oncology; space radiation protection high-LET particle radiation; protons; α-particles; C-ions; premature chromosome condensation (PCC); PCC assay; chromatin dynamics; chromothripsis; localized chromosome shattering; chromothripsis-like chromosomal rearrangements; RBE values; fingerprint of exposure; radiation oncology; space radiation protection
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MDPI and ACS Style

Pantelias, A.; Zafiropoulos, D.; Cherubini, R.; Sarchiapone, L.; De Nadal, V.; Pantelias, G.E.; Georgakilas, A.G.; Terzoudi, G.I. Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis. Cancers 2020, 12, 2336. https://doi.org/10.3390/cancers12092336

AMA Style

Pantelias A, Zafiropoulos D, Cherubini R, Sarchiapone L, De Nadal V, Pantelias GE, Georgakilas AG, Terzoudi GI. Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis. Cancers. 2020; 12(9):2336. https://doi.org/10.3390/cancers12092336

Chicago/Turabian Style

Pantelias, Antonio, Demetre Zafiropoulos, Roberto Cherubini, Lucia Sarchiapone, Viviana De Nadal, Gabriel E. Pantelias, Alexandros G. Georgakilas, and Georgia I. Terzoudi. 2020. "Interphase Cytogenetic Analysis of G0 Lymphocytes Exposed to α-Particles, C-Ions, and Protons Reveals their Enhanced Effectiveness for Localized Chromosome Shattering—A Critical Risk for Chromothripsis" Cancers 12, no. 9: 2336. https://doi.org/10.3390/cancers12092336

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