Genomic and Transcriptomic Analyses of Osteogenic Tumours of Bone

Abstract: Primary tumours of bone are heterogenous and infrequent neoplasms. Distinguishing between benign, intermediate and malignant entities can in some instances pose a clinical challenge. For some tumour types, there is still much to be learned about the genetic mechanisms that give rise to and drive these tumours forward. With the hope of improving diagnostic accuracy and treatment outcomes on the longer term, this thesis will deal with the genetic mutational mechanisms that characterise the primary osteogenic neoplasms osteoblastoma and osteosarcoma.In Article I, we show that a subgroup of non-FOS-rearranged, preferentially epithelioid osteoblastomas harbour homozygous loss of the NF2 gene. Additionally, we find a lower proportion of FOS-rearranged cases than previously reported and a high normal cell content.In Article II, we genetically characterise a rare chondroblastoma-like osteosarcoma/malignant phosphaturic mesenchymal tumour of bone. We detect a potentially targetable FN1-FGFR1 gene fusion and homozygous loss of the CDKN2A and DMD genes.In Article III, an RNA-sequencing screen of conventional osteosarcomas reveals that NTRK fusions are rare and most likely non-functional events.In Article IV, we demonstrate, for the first time, the existence of a recurrent gain-of-function mechanism involving the promoter region of the TP53 tumour suppressor gene in a subset of conventional osteosarcoma. We show that structural variants abrogate TP53 expression but also relocate its promoter region. By responding to ongoing DNA damage, it in turn leads to upregulation of known or putative oncogenes erroneously translocated into its vicinity.In Article V, we subdivide 12q-amplified osteosarcomas into four distinct groups and show that recurrent promoter swapping events involving the FRS2 and PLEKHA5 regulatory regions occur in many high-grade and dedifferentiated osteosarcomas with CDK4 and MDM2 amplification.In conclusion, this thesis will highlight the role chromosome remodelling plays in the development of primary osteogenic tumours of bone.