Radiation-Induced Chromosomal Breaks may be DNA Repair Fragile Sites with Larger-scale Correlations to Eight Double-Strand-Break Related Data Sets over the Human Genome

Brahme, Anders; Hultén, Maj; Bengtsson, Carin; Hultgren, Andreas; Zetterberg, Anders

doi:10.1667/rr15424.1

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…Fragile sites of tumor suppressor genes on chromosomes are highly sensitive to DNA damage. Reduced expression or deletion of these genes are highly correlated with the occurrence and development of tumors (23). In recent years, evidence for fragile sites is accumulating (24).…”

Section: Discussionmentioning

confidence: 99%

Plasma exosome-derived fragile-site associated tumor suppressor is a powerful predictor of prognosis in patients with ovarian cancer

Chen

Zhang

et al. 2021

Bosn J of Basic Med Sci

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Objective: To investigate the levels of plasma exosome-derived fragile-site associated tumor suppressor (FATS) and evaluate its predictive ability in ovarian cancer (OC) patients. Patients and Methods: Exosome-rich fractions were isolated from the plasma of enrolled 90 patients with OC. The levels of plasma exosome-derived FATS were detected with ELISA. Results: The levels of exosome-derived FATS in OC patient were significantly lower than in healthy controls (P < 0.001). The levels of plasma exosome-derived FATS were obviously higher in OC patients with low grade (1/2), FIGO stages I/II than high grade (3/4), stages III/ IV disease (P = 0.003; P < 0.001). The levels of plasma exosome-derived FATS were significantly higher in OC patients with no lymph node metastasis, no ascites than those with lymph node metastasis, ascites (both P < 0.001). The levels of plasma exosome-derived FATS were obviously higher in OC patients with CA-125 less than 35U/ml than more than 35U/ml (P < 0.001). Among all enrolled OC patients, both 5-DFS and 5-OS were shorter in patients who had low plasma exosome-derived FATS levels than that high levels (both P < 0.001). The AUROC of plasma exosome-derived FATS were 0.85(95% CI: 0.76-0.91) for 5-DFS, 0.91(95% CI: 0.83-0.96) for 5-OS prediction in patients with OC, respectively. Conclusions: Plasma exosome-derived FATS levels in OC patient were significantly down-regulated. Low levels of plasma exosome-derived FATS had close relationship with FIGO stages I/II, low grade, ascites, higher levels of CA-125, lymph node metastasis and prognosis of OC patients. Our findings may provide a new strategy in treating OC.

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Section: Discussionmentioning

confidence: 99%

Plasma exosome-derived fragile-site associated tumor suppressor is a powerful predictor of prognosis in patients with ovarian cancer

Chen

Zhang

et al. 2021

Bosn J of Basic Med Sci

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“…A recent study of radiation-induced chromosomal breakage sites (RIBs) found that they are often located at a new kind of "DNA repair fragile site" with large-scale correlations to seven other double-strand-break-related data sets over the whole human genome, such as HapMap recombination sites, MLH1 immunofluorescence and chiasma sites, classical common and rare fragile sites, copy number change (CNC) sites, regional low CpG density, and cancer-related genes [35]. Interestingly, in breast cancer patients with poor prognosis [36], on average, 69% of their CNCs are located at common radiation-induced chromosomal breakage sites covering less than 20% of the genome, whereas 49% of their CNCs are located in the more well-known common and rare fragile site regions covering approximately 27% of the genome.…”

Section: The Dna Damage Spectrum and Genetic Fragilitymentioning

confidence: 99%

Dual Nucleosomal Double-Strand Breaks Are the Key Effectors of Curative Radiation Therapy

Brahme,

Lorat

2023

Biophysica

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Most ionizing radiation produces δ-rays of ≈1 keV that can impart MGy doses to 100 nm3 volumes of DNA. These events can produce severe dual double-strand breaks (DDSBs) on nucleosomes, particularly in dense heterochromatic DNA. This is the most common multiply damaged site, and their probabilities determine the biological effectiveness of different types of radiation. We discuss their frequency, effect on cell survival, DNA repair, and imaging by gold nanoparticle tracers and electron microscopy. This new and valuable nanometer resolution information can be used for determining the optimal tumor cure by maximizing therapeutic effects on tumors and minimizing therapeutic effects on normal tissues. The production of DDSBs makes it important to deliver a rather high dose and LET to the tumor (>2.5 Gy/Fr) and at the same time reach approximately 1.8–2.3 Gy of the lowest possible LET per fraction in TP53 intact normal tissues at risk. Therefore, their intrinsic low-dose hyper-sensitivity (LDHS)-related optimal daily fractionation window is utilized. Before full p53 activation of NHEJ and HR repair at ≈½ Gy, the low-dose apoptosis (LDA) and LDHS minimize normal tissue mutation probabilities. Ion therapy should thus ideally produce the lowest possible LET in normal tissues to avoid elevated DDSBs. Helium to boron ions can achieve this with higher-LET Bragg peaks, producing increased tumor DDSB densities. Interestingly, the highest probability of complication-free cure with boron or heavier ions requires a low LET round-up for the last 10–15 GyE, thereby steepening the dose response and further minimizing normal tissue damage. In conclusion, the new high-resolution DSB and DDSB diagnostic methods, and the new more accurate DNA-repair-based radiation biology, have been combined to increase our understanding of what is clinically important in curative radiation therapy. In fact, we must understand that we already passed the region of optimal LET and need to go back one step rather than forward, with oxygen being contemplated. As seen by the high overkill and severely high LET in the distal tumor and the increased LET to normal tissues (reminding of neutrons or neon ions), it is therefore preferable to use lithium–boron ions or combine carbon with an optimal 10–15 GyE photon, electron, or perhaps even a proton round-up, thus allowing optimized, fractionated, curative, almost complication-free treatments with photons, electrons, and light ions, introducing a real paradigm shift in curative radiation therapy with a potential 5 GyE tumor boost, 25% increase in complication-free cure and apoptotic–senescent Bragg Peak molecular light ion radiation therapy.

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Radiation-Induced Chromosomal Breaks may be DNA Repair Fragile Sites with Larger-scale Correlations to Eight Double-Strand-Break Related Data Sets over the Human Genome

Cited by 2 publications

References 41 publications

Plasma exosome-derived fragile-site associated tumor suppressor is a powerful predictor of prognosis in patients with ovarian cancer

Plasma exosome-derived fragile-site associated tumor suppressor is a powerful predictor of prognosis in patients with ovarian cancer

Dual Nucleosomal Double-Strand Breaks Are the Key Effectors of Curative Radiation Therapy

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