S2588
Radiobiology – Normal tissue radiobiology
ESTRO 2026
primary concerns are the long-term neurological consequences, including neurocognitive decline, neurodegeneration, vasculopathy and secondary neoplasms. To date, there are no studies that have systematically explored the radiation- or drug-induced molecular genetic signature in the developing human brain at cell type-specific resolution. To address this gap, we present clinicopathological and emerging experimental data on a unique cohort of ten children with brain tumours who, together with their families, generously donated postmortem tissue for research to the Oxford Brain Bank. Material/Methods: Samples from post-mortem cerebellar tissue and age- matched controls were stained with a panel of markers to assess the DNA damage ( γ H2AX, HP1 γ ) autophagy (p62), gliosis (GFAP), vascular changes (EVG, SMA), and microglial activation (Iba1, CD68). H&E staining was used to evaluate the histopathological changes. Quantitative and qualitative assessments were performed to identify patterns of radiation- induced changes to the tissue.In parallel, single- nucleus RNA sequencing (snRNA-seq) analysis is being undertaken to investigate transcriptional signatures associated with radiation exposure, with a focus on inflammation, DNA damage response, and vascular- related pathways. Results: Compared to controls, irradiated human cerebellar samples exhibited increased microglial activation, elevated DNA damage markers, and morphological abnormalities including white matter oedema and Purkinje cell loss on H&E staining. While the immunohistochemistry (IHC)findings suggest persistent neuroinflammatory and DNA damage responses, IHC provides a limited measure of protein expression, for example diffuse γ H2AX nuclear staining may not accurately reflect DNA double-strandbreaks, as noted in previous neuropathological studies1.The snRNA- seq analysis will enable a higher-resolution characterisation of transcriptional changes underpinning these histopathological observations. Conclusion: Paediatric post-mortem analysis reveals radiation- induced cellular and molecular alterations in the cerebellum. However, IHC is a semi-quantitative and sometimes subjective measure of protein expression, particularly for γ H2AX. To overcome these limitations, snRNA-seq is being implemented in parallel to identify gene expression signatures associated with radiation-induced inflammation and DNA damage. Integrating transcriptomic and histopathological data will refine our understanding of cell- and region- specific vulnerability to radiotherapy, ultimately helping to mitigate neurocognitive deficits in children with brain tumours.
regulation of cAMP-mediated signaling (FDR = 6.1E-11).
Conclusion: This study replicated genetic variants associated with late radiation-induced hematuria, first discovered from GWAS among cohorts of the RGC. The bioinformatic analysis identified plausible biological mechanisms impacting the risk of hematuria that warrant further functional characterization. References: [1] Barnett GC, Thompson D et al. A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity. Radiotherapy and Oncology, 111(2):178-185, 2014.[2] Farazi M, Yang X et al. A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer. Cancer Epidemiol Biomarkers Prev, 34(5):795- 804, 2025. Keywords: Radiation-induced hematuria, GWAS, Poster Discussion 5061 Mechanisms of neurotoxicity in childhood cancer therapy. Claire Lewis 1 , Casmir Turnquist 1 , Hannah Brooks 1 , Shaun Wilson 2 , Olaf Ansorge 1 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. 2 Oxford University Hospitals, John Radcliffe Hospital, Oxford, United Kingdom Purpose/Objective: Radiotherapy and chemotherapy are essential parts of childhood cancer treatment, contributing to the control of otherwise lethal tumours. However, these therapies often result in both acute and late effects, particularly on the developing nervous system. The
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