Brain-Derived Circulating DNA as a Biomarker for Radiotherapy-Induced Brain Damage

Radiotherapy is a common and effective treatment for brain metastases. However, it is commonly associated with central nervous systems (CNS) toxicity mediated by both neuronal cell death and white matter changes involving astrocytes and oligodendroglia damage, leading to progressive and irreversible disability. Current methods detect treatment-induced CNS toxicity only when it crosses clinical thresholds without biomarkers for preclinical neurotoxicity detection. We explored the utility of cell-free circulating DNA (cfDNA), shed from dying cells, for sensitive detection of brain cell death in the context of brain metastases. Using comparative methylome analysis we have identified 13 genomic loci with neurons, oligodendrocytes and astrocytes-specific DNA methylation patterns and measured in plasma of patients suffering from traumatic and ischemic brain damage. Preliminary results show elevation of cfDNA derived from neurons, oligodendrocytes and astrocytes in patients with following radiotherapy suggesting widespread damage induced by treatment of brain metastases compared with extremely low background in healthy individuals. A patient suffering from an acute central facial paralysis during radiotherapy shows a clinical correlation of brain-derived cfDNA levels with neurological impairment. Tissue-specific cfDNA may serve as a novel circulating biomarker for brain cell death in patients suffering from brain metastasis, reflecting brain cell death and tissue damage associated with radiotherapy.