Exploring tumour evolution through mutational patterns in bone tumours

Cancer is a continuation of the evolutionary process on a cellular scale. The mutations that define this evolutionary process show a marked variety of complexity, which I have explored in this work. First, I have explored the genomics of osteoblastoma, a rare benign bone tumour. This work, for the first time, demonstrates that osteoblastoma and the related entity, osteoid osteoma, are defined by structural rearrangements in the AP-1 family of genes, FOS and FOSB. This original work is the first report of a FOS mutation in a human bone-forming tumour since its discovery as one of the archetypal proto-oncogenes, forming the basis of a much-needed diagnostic test. Giant cell tumours (GCTs) of bone are characterised by an H3.3 gene mutation. I have explored a group of benign (GCTs), benign metastasising and malignant bone tumours which possess this mutation. Methylation profiling and evolutionary analysis suggest that malignant tumours have transformed from GCTs, acquiring replicative immortality or an additional epigenetic regulatory mutation. In contrast, my analyses show that benign metastatic disease can occur without any additional mutational changes. Finally, I have studied complex mutational events more broadly in cancer and benign neoplastic disease. I reported chromothripsis and chromoplexy in malignant GCTs and osteoblastoma respectively for the first time. I explored the detection, frequency and evolutionary onset of chromoplexy in a collection of 2,626 human tumours. Found across almost all cancer types, the particularly striking and novel finding was the high frequency of chromoplexy in thyroid cancers, creating many of the known driver fusions. Altogether, focusing on primary bone tumours, I have demonstrated how both simple and complex mutational events can define the earliest steps in tumour evolution. The analysis of complex patterns of mutation can also give new insights into the patterns of progression of both malignant and metastatic disease