P03.08.A HIGH-DIMENSIONAL CHARACTERISATION OF THE CELLULAR AND MOLECULAR CHANGES IN THE HUMAN BRAIN AFTER RADIOTHERAPY

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 25; no. Supplement_2; p. ii38
• Main Authors: Millner, T O, Panday, P, Pomella, N, Badodi, S, Marino, S
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 08-09-2023
• Subjects: POSTER PRESENTATIONS
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noad137.119

Abstract
BACKGROUND
In the UK ~40,000 intrinsic and metastatic brain tumours are diagnosed each year. Although targeted radiotherapy (RT) is integral to increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT treatment epigenetic changes occur in the neoplastic tissue, but few studies have assessed these in non-neoplastic brain tissue and results are highly variable.
MATERIAL AND METHODS
To explore the effects of RT on patient-specific methylation, we retrospectively identified 19 samples, mainly metastatic tumours, that had undergone stereotactic-RT followed by resection, and contained peri-lesional brain tissue, as well as 14 controls. Peri-lesional brain was micro-dissected, followed by DNA methylation profiling and RNA-sequencing.
RESULTS
Clustering of DNA methylation data showed distinct patterns between the two groups, whilst RNA-seq revealed 1,887 differentially expressed genes. Pathway analysis with GSEA identified differentially represented pathways, including: innate immune system, trans-synaptic signalling, olfactory signalling, regulation of supramolecular fibre organisation, and pattern specification. Computational deconvolution of cellular composition showed increased activated dendritic cells and B-cells, and reduced smooth muscle cells and several sub-sets of astrocytes in the RT samples.
CONCLUSION
We are currently further investigating these findings using spatial transcriptomics and proteomics to produce the first high-dimensional characterisation of the irradiated human brain. This will also provide the first direct evidence of epigenetic dysregulation after targeted-RT, and assess novel epigenetically-regulated genes, which will be validated with single cell tissue-based imaging techniques. A range of epigenetic-based drugs are undergoing clinical trials and we aim to identify targets for radiomitigation in brain tumour patients.