These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.
The SYT-SSX fusion protein that results from the X,18 translocation is an appealing target, as are the proteins overexpressed in synovial sarcoma: bcl-2, EGFR, and HER-2/neu.
Synovial sarcomas (SS) are characterized by a chromosomal translocation t(X;18)(p11.2;q11.2) which usually fuses the SYT gene from chromosome 18 to SSX1 or SSX2 genes on chromosome X.
Substantial evidence indicates that the characteristic SS18-SSX fusion gene may play an important role in synovial sarcoma development and progression.
There was a significant relation (P=0.003) between histologic subtype (monophasic vs. biphasic) and SSX1 or SSX2 involvement in the fusion transcript: all 12 biphasic synovial sarcomas had a SYT-SSX1 fusion transcript, and all 16 tumors that were positive for SYT-SSX2 were monophasic.
There was a significant relation (P=0.003) between histologic subtype (monophasic vs. biphasic) and SSX1 or SSX2 involvement in the fusion transcript: all 12 biphasic synovial sarcomas had a SYT-SSX1 fusion transcript, and all 16 tumors that were positive for SYT-SSX2 were monophasic.
In both cases, reverse transcription-polymerase chain reaction using ribonucleic acid extracted from formalin-fixed, paraffin-embedded tissues detected SYT-SSX2 fusion gene transcripts, which are characteristic molecular findings of synovial sarcoma.
The t(X;18)(p11.2;q11.2), which results in fusion of the SYT gene at 18q11 with the SSX1, SSX2, or (rarely) SSX4 gene is a primary genetic event in 90% of SS.
Ultimately, an immunohistochemical stain for TLE-1 demonstrated diffusely strong nuclear positivity and molecular studies showed the presence of the t(X; 18) SYT/SSX1 translocation confirming the diagnosis of SS.
In conclusion, our findings demonstrate differentially expressed genes for the 2 major gene fusion variants in SS, SS18/SSX1 and SS18/SSX2, and thereby suggest that these result in different downstream effects.
Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor.
We conclude that the findings suggest that the type of SYT-SSX fusion transcript determines the proliferation rate and is an important predictor of clinical outcome in patients with SS.
Real-time RT-PCR assays specific for Ewing's sarcoma (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-ETV4, and EWS-FEV), synovial sarcoma (SYT-SSX1 and SYT-SSX2), and rhabdomyosarcoma (PAX3-FKHR and PAX7-FKHR) were tested across the samples.
Isobaric tags for relative and absolute quantitation (i-TRAQ) analyses identified approximate 1700-2,000 proteins regulated by the SS18/SSX fusion in each SS cell line.
As a result of the synovial sarcoma associated t(X;18) translocation, the human SYT gene on chromosome 18 is fused to either the SSX1 or the SSX2 gene on the X chromosome.