In France, 196,000 patients received radiotherapy in 2017 to treat cancer, 12% more than in 2012[1]. Although oncology is increasingly equipped with tools to fight the disease (e.g. chemotherapy, immunotherapy, targeted therapies, and hormone therapy), radiotherapy remains a proven and effective technique. However, it is not without side effects, particularly for healthy tissues in the vicinity of the tumor. Researchers from the CEA-Jacob and the Claude Bernard University have now identified a molecular signature for ionizing radiation sensitivity in patients presenting significant side effects after radiotherapy treatment.

There are two levels of radiosensitivity: the first, at the cellular level, is related to the rate of cell death and the ability of cells to repair damaged DNA; the second, at the tissue level, is macroscopic and concerns the development of severe lesions in irradiated tissues, whereas the same dose delivered to the majority of the population causes no effect or only mild transient effects. Although it is estimated that 5-15% of patients undergoing radiotherapy experience severe side effects in non-cancerous tissues, the molecular mechanisms involved are still poorly understood, and the links between cellular and tissue radiosensitivity are disputed.

Scientists at the CEA-Jacob and their partners compared what happens in the skin fibroblasts[2] of a cohort of patients who developed severe side effects in certain tissues to the fibroblasts of control individuals. The former show greater cell death, particularly linked to serious DNA damage repair defects. These results strengthen the links between cellular, tissue and clinical radiosensitivity.

At the molecular level, analysis of the transcriptome[3] of these cells was used to identify 540 genes whose expression was deregulated in the fibroblasts of radiosensitive patients. The researchers were particularly interested in the NFATC2 gene, which is associated with the regulation of apoptosis and the cell cycle. They found a correlation between the expression of this gene and cell survival following irradiation. In contrast, they demonstrated that the repression of NFATC2 leads to DNA repair defects. These results show for the first time that NFATC2 contributes to the ionizing radiation response of cells, as well as to radioresistance.

This study highlights a molecular ionizing radiosensitivity signature in patients with significant side effects following radiotherapy. It is part of the search for new cellular and molecular strategies to facilitate the identification of radiosensitive patients and to better predict the harmful consequences of exposure to ionizing radiation in healthy tissues.