Synovial sarcoma : molecular, biological and clinical implications

Sammanfattning: Synovial sarcoma is a rare but mostly aggressive soft tissue tumor that mainly affects children and young adults. The tumor usually occurs in the vicinity of large joints, and may be subdivided into a classical biphasic type, a monophasic type or a poorly differentiated type, depending on histomorphological appearance. Synovial sarcoma is cytogenetically characterized by the recurrent and specific translocation t(X, 18)(pl 1,2;q1 1.2), which results in fusion of the 5'part of the SS18 gene, and the 3'part of either the SSX1 SSX2 or SSX4 gene. Since the resulting fusion gene SS18-SSX is specific for synovial sarcoma, it constitutes a valuable molecular tool at diagnosis. In this thesis, a previously SS18-M negative case is described, where an unusual breakpoint variant was detected after method optimization, thereby confirming diagnosis. The case provided molecular information of the oncogenic properties of SS18-SSX, since the unusual breakpoint resulted in alteration of the predicted amino acid sequence, potentially encoding an altered fusion protein. A renal tumor was reinvestigated after a highly aggressive behavior, usually not compatible with the originally diagnosis of hemangiopericytoma. After molecular confirmation of the presence of SS18-SSX, the new diagnosis was synovial sarcoma. These cases underline the usefulness and necessity of molecular investigations of suspected, but due to unexpected fusion breakpoints or unusual locations not confirmed synovial sarcomas. In order to investigate downstream events of SS18-SSX, an antisense strategy was used in combination with a cDNA microarray. It was possible to compare the gene expression profile of SS18-SSX inhibited cells with non-inhibited, showing altered expression levels of genes involved in cancer-relevant functions like cell proliferation, apoptosis and DNA-repair. It has recently been shown that SS18-SSX is able to stabilize expression of cyclin D 1, and that IGF-1R expression is associated with poor prognosis in synovial sarcoma. These aspects were further investigated here, suggesting a proliferative role of SS18-SSX since its expression allowed cells to remain in cycle even in the absence of mitogenic signals. On the other hand, inhibition of the IGF-1 R caused massive cell death. A potential therapeutic strategy could use the continued cell cycle and kill the cells by inhibition of IGF 1 - 1 R. Results presented in this thesis provide clues to the molecular, biological and clinical consequences of SS18-SSX. This information may be relevant for the development of specific therapeutic strategies against the highly malignant disease.