Integrative omics analyses of sarcomas with complex genomes: from molecular characterization to therapeutic strategies

Abstract

Complex genome sarcomas are a subgroup of sarcomas characterized by extensive genetic alterations, including copy number variations and structural variants. The genomes of those tumors are very chaotic, containing numerous large-scale genetic alterations. These tumors show high interpatient heterogeneity. This makes it difficult to understand the oncogenesis and find targets for treatment, which is needed to make progress in personalized therapy. On the other hand, sarcomas with complex genomes are more likely to present evidence of anti-tumor immunity, which could be harnessed for immunotherapeutic strategies. Therefore, the aim of this thesis was to molecularly profile sarcomas with a complex genome, as well as their tumor microenvironment (TME). The primary focus was on the two most common bone sarcoma types: osteosarcoma and chondrosarcoma. Subsequently, a prospective study was conducted on various advanced sarcomas with complex genomes to identify potential therapies based on molecular alterations and TME composition. Together, the following chapters of this thesis provide a comprehensive analysis of the molecular landscape and immune microenvironment of complex genome sarcomas, offering insights that could guide future (immuno)therapeutic strategies.