DNA Methylation Alterations Drive Neuroinflammation After CNS Radiotherapy

Overview

Targeted CNS radiotherapy induces significant DNA methylation changes in peri-lesional brain tissue, predominantly hypomethylation, which correlates with altered gene expression and neuroinflammatory microenvironments. These epigenetic modifications are also recapitulated in cerebral organoid models, implicating DNA methylation dysregulation as a key mechanism underlying radiotherapy-induced neurotoxicity.

Background

Radiotherapy is a cornerstone treatment for brain metastases and other focal neurological conditions but is associated with both short- and long-term side effects including neuroinflammation and cognitive impairment. While epigenetic changes in tumor tissue post-radiotherapy are documented, the impact on surrounding non-neoplastic brain tissue remains unclear. Understanding these molecular alterations is critical to developing strategies that protect normal brain tissue without compromising tumor control.

Data Highlights

Key Findings

• Distinct DNA methylation profiles differentiate irradiated from non-irradiated peri-lesional brain tissue.
• Majority (75%) of differentially methylated regions are hypomethylated following radiotherapy.
• Epigenetic changes are enriched in regulatory genomic regions such as promoters and 5′ untranslated regions.
• Irradiated tissue shows increased microglia/macrophage infiltration and reduced peripheral immune and endothelial cells.
• Similar DNA methylation alterations and neuropeptide upregulation are observed in cerebral organoid models post-irradiation.
• Epigenetic dysregulation likely contributes to neuroinflammation and neurotoxicity after CNS radiotherapy.

Clinical Implications

These findings highlight DNA methylation alterations as a mechanistic driver of neuroinflammation and neurotoxicity following targeted CNS radiotherapy. Monitoring epigenetic changes could inform risk stratification for radiotherapy side effects. Furthermore, targeting epigenetic regulators may offer novel therapeutic avenues to mitigate neurotoxic effects while preserving anti-tumor efficacy.

Conclusion

Targeted CNS radiotherapy induces widespread DNA methylation changes that promote neuroinflammatory microenvironments and neurotoxicity. Epigenetic dysregulation represents a promising target to reduce adverse effects of radiotherapy on normal brain tissue.

References

1. Kular et al. 2022 -- Alteration of DNA Methylation Drives Neuroinflammation Following Targeted CNS Radiotherapy