Landscape of nucleosome repositioning in glioblastoma multiforme

Glioblastoma (GBM) is classified as a grade IV astrocytoma, characterised by its aggressive nature and poor prognosis. It represents a major problem in oncology given its abysmal survival rate and lack of effective treatment options to cure the malignancy and prevent relapses. The current methods for diagnostics generally include magnetic resonance imaging (MRI) followed by histopathological confirmation via analysis of tissue biopsy, which is an invasive method. Furthermore, such diagnostics methods often result in brain cancer detection at late stages. One alternative method is liquid biopsy, which uses bodily fluids, e.g. blood plasma or cerebral spinal fluid (CSF), to extract and analyse cell-free DNA (cfDNA) to detect genomic or epigenomic alterations characteristic of the disease. The aim of this project was to analyse a specific type of change in cfDNA reflecting nucleosome positioning in the cells of origin, which may be used for GBM diagnostics. Using data from a cohort of 10 GBM patients, I have analysed nucleosome positioning in paired normal/tumour brain tissues and the corresponding cfDNA. I compared nucleosome profiles from these three sources around binding sites of transcription factors (TFs) and developed new ways of data normalisation and visualisation with heatmaps and clustering. This work provided a shortlist of TFs that can be used as biomarkers and highlighted the challenges encountered in liquid biopsies of GBM and suggested new approaches to overcome these.