CAESAR: Comprehensive Analysis of Epigenetic Heterogeneity in SARcoma

Despite progress in the histological classification of the different subtypes of sarcoma, the clinical outcome for OS patients has not improved the last 40 years. To change this, it is essential to have a comprehensive understanding of the molecular basis of OS. This study is conducted on a unique OS cohort with 1-8 samples collected from each OS tumour and excellent clinical follow-up. This project will generate novel knowledge of the epigenomes of OS tumours in general. It will give insight to the tumours' epigenetic heterogeneity and clonal evolution, which have both been causally linked to resistance to therapy. Findings will be integrated with genomic and transcriptomic data from the same samples to understand fully the underlying biology, and for the first time give a complete pictur

I will interrogate DNA methylation heterogeneity at single-nucleotide level using enhanced reduced-representation bisulfite sequencing (RRBS) - targeting up to 4 million CpG sites. Using a new Bayesian epiallele detection algorithm, I will determine for the first time whether locally disordered methylation exists in OS. By deriving intra-tumour DNA methylation heterogeneity indexes, I will characterise tumour evolution and determine associations between heterogeneity and the presence of particular driver mutations. Notably, the generated methylome profiles will be correlated to whole genome sequencing (WGS) and RNA-seq data together with clinical outcomes to obtain a better understanding of the underlying molecular mechanisms that govern the initiation and development of OS.