Pathogenetic Mechanisms in Soft Tissue Tumors

Sammanfattning: Soft tissue tumors (STT) constitute a heterogeneous group of tumors that arise in tissues of mesenchymal origin. They are currently classified according to morphology and resemblance to normal tissue into over 100 subtypes. Differentiation between the different subtypes can sometimes be difficult, and along with the fact that little is known about the mechanisms of STT development, this makes adequate diagnosis and treatment challenging. In the present thesis, three different pathogenetic mechanisms involved in STT development are investigated and the included studies illustrate each of these mechanisms. In articles I and II, sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low grade fibromyxoid sarcoma (LGFMS) are genetically characterized by the predominant fusion gene variants they harbor. We conclude that the respective fusion genes found in SEF, hybrid SEF/LGFMS and LGFMS are most likely the primary tumorigenic event and that the clinical differences can be explained by the difference in genomic imbalances and aberrations. Additionally, DMD and CD24 are identified as potential therapeutic targets in SEF. In article III, the genetics of angiolipomas are investigated by ultra-deep DNA-sequencing and RNA-sequencing, identifying low-level PRKD2 mutations as the sole genetic abnormality. We demonstrate that the mutations are enriched in mature fat cells and that they affect the catalytic domain of PRKD2, leading to increased proliferation of adipocytic cells and formation of a distorted capillary network. Thus, PRKD2 mutations are probably the driver events in angiolipoma formation. In article IV; we establish that ILMS is a distinct nosologic entity characterized by non-random near-haploidization and few other somatic mutations. Our results indicate that near-haploidization is the main tumorigenic event. We also show that ILMS has a primitive myogenic gene expression signature, providing support for it being classified as a myogenic tumor.In conclusion, studying the mechanisms behind sarcoma development enables the identification of characteristic or even specific diagnostic markers and potential therapeutic targets. This paves the way for individualizing cancer treatment and thus has major implications for treatment outcome and patient well-being.

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