Induction of Micronuclei in Cervical Cancer Treated with Radiotherapy

Abstract

Micronuclei (MN) trigger antitumor immune responses via the cyclic GMP-AMP synthase-signaling effector stimulator of interferon genes (cGAS-STING) pathway. Radiotherapy induces MN in peripheral blood lymphocytes. However, data for solid tumors are lacking. Here, we analyzed MN post-radiotherapy in solid tumor samples. Tumor biopsy specimens were obtained from seven prospectively recruited patients with cervical cancer, before treatment and after receiving radiotherapy at a dose of 10 Gy (in five fractions). The samples were stained with 4′,6-diamidino-2-phenylindole dihydrochloride, and 200 nuclei per sample were randomly identified and assessed for the presence of MN or apoptosis, based on nuclear morphology. The median number of MN-harboring nuclei was significantly greater in samples from patients treated with radiotherapy than in pre-treatment samples (151 (range, 16–327) versus 28 (range, 0–61); p = 0.015). No significant differences in the number of apoptotic nuclei were observed between pre-treatment and 10 Gy samples (5 (range, 0–30) versus 12 (range, 2–30); p = 0.30). This is the first report to demonstrate MN induction by radiotherapy in solid tumors. The results provide clinical evidence of the activation of antitumor immune responses by radiotherapy.

Expression of non‑homologous end joining factor, Ku80, is negatively correlated with PD‑L1 expression in cancer cells after X‑ray irradiation

“…To date, multiple pathways regarding PD-L1 expression after DNA damage have been suggested, such as cytosolic sensors cGAS/RIG-I transducing immune-activating signal releasing interferon stimulate genes following the recognition of cytosolic DNA/RNA released from the nucleus (10)(11)(12). Since radiotherapy can generate micronuclei that should contain DNA/RNA (33), further studies are required to examine the involvement of this pathway.…”

Exacerbated Inflammatory Gene Expression After Impaired G2/M-Checkpoint Arrest in Fibroblasts Derived From a Patient Exhibiting Severe Adverse Effects

“…ATR-Chk1 and signal mediator proteins, such as 53BP1 and MDC1, contribute to the maintenance of G2/M arrest after IR. 17 Micronuclei formation has also been observed in human tumor cells after RT, 18 highlighting the occurrence of these cellular responses in patients during RT. Here, we comprehensively examined micronuclei formation, G2/M-arrest, DNA damage signaling and repair, and inflammatory gene expression in dermal fibroblasts from a patient with a severe esophageal inflammatory phenotype during RT.…”

The risk of cancer following high, and very high, doses of ionising radiation

“…Studies of molecular and genetic markers and genome-wide association studies (GWAS) offer the promise of better understanding the mechanistic processes involved in therapy-related cancer (Morton et al 2017b); Rutten and Badie (2021) have provided a précis of the current status of radiation biomarkers. It is established that chromosome translocation frequencies in peripheral blood lymphocytes are a reflection of dose to the ABM if measured in stable cells (Tawn and Whitehouse 2003), and micronuclei frequencies in solid cancer cells following radiotherapy have recently been reported by Kobayashi et al (2020). Behjati et al (2016), Kocakavuk et al (2021), Morton et al (2020) and Haddy et al (2014) have investigated various mutational signatures of the involvement of radiation in second primary cancer, while Morton et al (2017a) conducted a GWAS and Opstal- van Winden et al (2019) a study of single-nucleotide polymorphisms in investigations of the susceptibility of patients to radiation-related breast cancer.…”