Disruption of DNA methylation underpins the neuroinflammation induced by targeted CNS radiotherapy

Targeted radiotherapy is integral to the increasing survival of cancer patients; however, it has significant side effects, the underlying cellular and molecular mechanisms of which are ill-defined. It is well documented that targeted radiotherapy induces epigenetic changes in neoplastic tissue, which impacts tumour evolution; however, whether epigenetic deregulation also occurs in the surrounding non-neoplastic tissue and contributes to the occurrence of side effects is unknown. We characterized the DNA methylome in a unique cohort of irradiated peri-lesional brain tissue samples and integrated it with gene expression analysis at the spatial level. We show differences in DNA methylation patterns in irradiated brain tissue and identify specific inflammatory micro-environmental niches and their regulatory neuropeptides after irradiation. Finally, we show in a cerebral organoid model, that the same neuropeptides are upregulated as well as similar DNA methylation alterations and disruption of the DNA methylation machinery, in keeping with the interpretation that epigenetic dysregulation plays a role in neurotoxicity, hence raising the possibility it could represent a novel target for the reduction of radiotherapy side effects.