Abstract 03: The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis

Synovial sarcoma, the most common soft-tissue sarcoma in young adults bears a t(X;18) translocation that generates a fusion between SS18 (formerly SYT) and an SSX gene. SS18-SSX1 and SS18-SSX2 differ by only 13 amino acids. Clinically, SS18-SSX1 is more common, portends a worse prognosis, and demonstrates increased prevalence of biphasic histology. We conditionally expressed each fusion in otherwise identical mouse models, unexpectedly finding SS18-SSX2 to be more sarcomagenic than SS18-SSX1 and equally prone to biphasic histology. This suggested that coding sequence does not account for clinical differences between the fusions. Reanalysis of patient series found a gender bias in the prevalence of SS18-SSX2-expressing tumors, suggesting an X-linked effect and implicating the loss of native SSX2 by translocation as a hinderance to SS18-SSX2-driven synovial sarcomagenesis in males. Next, we confirmed that human synovial sarcomas almost universally express native SSX2, but not SSX1 and knock-down of native SSX2 in human synovial sarcoma cell lines blunted proliferation whereas overexpression of SSX2 enhances cell proliferation. In conclusion, we hypothesize that SSX2 facilitates sarcomagenesis in SS18-SSX1-expressing tumors and because our model of SS18-SSX2-expressing mice does not disrupt native SSX2 it recapitulates the prevalence and phenotype of SS18-SSX1 tumors. Citation Format: Kevin B. Jones, Jared J. Barrott, Huifeng Jin, Malay Haldar, Mario R. Capecchi. The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 03.