Genetic drivers and cells of origin in sarcomagenesis

Sarcoma comprises a group of malignancies that includes over 100 individual disease entities. Type-specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasingly molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.