The biological role and clinical impact of SYT-SSX fusion gene and IGF-1R in synovial sarcoma

Synovial sarcoma, which is a highly malignant soft tissue tumour occurring mainly in young and middle-aged adults, is characterized by the translocation t(X; 18)(p 11.2; q 11.2). This translocation results in a fusion between the SYT gene on chromosome 18 and SSX1 or SSX2 on the X chromosome with the formation of new chimeric genes, SYT-SSX1, SYT-SSX2. The unique chromosomal translocation t(X:18)(p11.2:q11.2) is presented in more than 90% of the synovial sarcoma cases, and is believed to be an early and key molecular event playing a crucial role in tumour development and progression. This thesis aims to explore the biological role and clinical impact of SYT-SSX fusion genes in synovial sarcoma.

A novel fusion gene, SYT-SSX4, was identified in a case of typical synovial sarcoma, and harbours the same breakpoint regions as in SYT-SSX1 or SYT-SSX2.

The potential relevance between the clinical outcome and SYT-SSX fusion types was investigated in 33 patients with primary synovial sarcoma. The 5-year metastasisfree survival for patients with SYT-SSX1 was 42% vs. 89% for patients with SYT-SSX2 with a hazard ratio (HR) of 7.4 (95% CI 1.5-36, log-rank P-0.004). There was a significant association between SYT-SSX1 and high tumour proliferation rate (P=0.02). Furthermore, we found a significant correlation between SYT-SSX1 and high expression of cyclin A and D1 in a large number of localized synovial sarcoma tumours. Those data suggest that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 fusion type is due to an accelerated tumour cell proliferation.

Overexpression of IGF-1R was found in about 50% synovial sarcoma tumours. These tumours exhibited a significantly increased incidence of lung metastasis (P-0.01). However, there was no correlation between the IGF-1R level and SYT-SSX fusion types, suggesting that they are independent of each other.

Antisense oligonucleotides (AS) to SYT-SSX mRNA expression rapidly and drastically decreased cyclin D1 expression and subsequently inhibited cell growth. The decrease in cyclin D1 expression was found to be primarily due to an increased degradation of the cyclin D1 protein via ubiquitin-dependent pathway, but was independent of the glycogen synthetase kinase-3beta pathway.

In conclusion, this study suggests that SYT-SSX and IGF-1R are crucial for tumour cell proliferation and progression of synovial sarcoma, and may provide important predictive and therapeutic targets for this disease. Especially, a therapeutic targeting of SYT-SSX would be an ideal strategy since it would specifically ablate the tumour growth while sparing the normal tissues.

List of scientific papers

I. Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J, Uhlen M, Larsson O (1999). "A novel fusion gene, SYT-SSX4, in synovial sarcoma. " J Natl Cancer Inst 91(11): 974-5
https://pubmed.ncbi.nlm.nih.gov/10359553

II. Nilsson G, Skytting B, Xie Y, Brodin B, Perfekt R, Mandahl N, Lundeberg J, Uhlen M, Larsson O (1999). "The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. " Cancer Res 59(13): 3180-4
https://pubmed.ncbi.nlm.nih.gov/10397263

III. Xie Y, Skytting B, Nilsson G, Brodin B, Larsson O (1999). "Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype. " Cancer Res 59(15): 3588-91
https://pubmed.ncbi.nlm.nih.gov/10446966

IV. Xie Y, Skytting B, Nilsson G, Gasbarri A, Haslam K, Bartolazzi A, Brodin B, Mandahl N, Larsson O (2002). "Syt-SSX is critical for cyclin D1 expression in synovial sarcoma cells: A gain-of-function of the t(X;18) (p11.2;q11.2) translocation." Cancer Res (In Print)

V. Xie Y, Skytting B, Nilsson G, Grimer R, Mangham C, Fisher C, Shipley J, Bjerkehagen B, Myklebost O, Larsson O (2002). "The SYT-SSX1 fusion type of synovial sarcoma is associated with increased expression of cyclin A and D1. A link between t(X;18) (p11.2; q11.2) and the cell cycle machinery." Oncogene (Accepted)