Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus.
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The t(X;18)(p11.2;q11.2) chromosomal translocation commonly found in synovial sarcomas fuses the SYT gene on chromosome 18 to either of two similar genes, SSX1 or SSX2, on the X chromosome. The SYT protein appears to act as a transcriptional co-activator and the SSX proteins as co-repressors. Here we have investigated the functional domains of the proteins. The SYT protein has a novel conserved 54 amino acid domain at the N-terminus of the protein (the SNH domain) which is found in proteins from a wide variety of species, and a C-terminal domain, rich in glutamine, proline, glycine and tyrosine (the QPGY domain), which contains the transcriptional activator sequences. Deletion of the SNH domain results in a more active transcriptional activator, suggesting that this domain acts as an inhibitor of the activation domain. The C-terminal SSX domain present in SYT-SSX translocation protein contributes a transcriptional repressor domain to the protein. Thus, the fusion protein has transcriptional activating and repressing domains. We demonstrate that the human homologue of the SNF2/Brahama protein BRM co-localizes with SYT and SYT-SSX in nuclear speckles, and also interacts with SYT and SYT-SSX proteins in vitro. This interaction may provide an explanation of how the SYT protein activates gene transcription. (+info)
SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex.
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Chromosome translocation t(X;18)(p11.2;q11.2) is unique to synovial sarcomas and results in an 'in frame' fusion of the SYT gene with the SSX1 or closely-related SSX2 gene. Wild-type SYT and SSX proteins, and the SYT-SSX chimaeric proteins, can modulate transcription in gene reporter assays. To help elucidate the role of these proteins in cell function and neoplasia we have performed immunolabelling experiments to determine their subcellular localization in three cell types. Transient expression of epitope-tagged proteins produced distinctive nuclear staining patterns. The punctate staining of SYT and SYT-SSX proteins showed some similarities. We immunolabelled a series of endogenous nuclear antigens and excluded the SYT and SYT-SSX focal staining from association with these domains (e.g. sites of active transcription, snRNPs). In further experiments we immunolabelled the Polycomb group (PcG) proteins RING1 or BMI-1 and showed that SSX and SYT-SSX proteins, but not SYT, co-localized with these markers. Consistent with this we show that SSX and SYT-SSX associate with chromatin, and also associate with condensed chromatin at metaphase. Noteably, SSX produced a dense signal over the surface of metaphase chromosomes whereas SYT-SSX produced discrete focal staining. Our data indicate that SSX and SYT-SSX proteins are recruited to nuclear domains occupied by PcG complexes, and this provides us with a new insight into the possible function of wild-type SSX and the mechanism by which the aberrant SYT-SSX protein might disrupt fundamental mechanisms controlling cell division and cell fate. (+info)
Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group.
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Soft-tissue tumors have proved to be a fruitful area for the identification of reproducible cytogenetic aberrations, especially among pediatric round-cell sarcomas and lipomatous tumors. Thus far, however, data regarding sarcomas of monomorphic spindle cell type have been limited and somewhat disappointing, with the notable exception of synovial sarcoma. As part of an ongoing international collaborative study, 130 karyotyped spindle-cell sarcomas were reviewed and classified histologically, without knowledge of the clinical and karyotypic data, with the aim of identifying objective correlations between morphology, karyotype, and clinical parameters. Clonal chromosomal abnormalities were identified in 82 cases studied (63%), but only in the group of synovial sarcomas was there clear correlation between the cytogenetic findings, in the form of a consistent t(X;18)(p11;q11), and morphology. Among leiomyosarcomas (41 cases) and malignant peripheral nerve sheath tumors (MPNSTs; 27 cases) as well as in individual examples of rarer entities, there was a general tendency for karyotypic complexity associated with frequent loss or rearrangement of chromosome arms 1p, 10p, 11q, 12q, 17p, and 22q. Rearrangements of 17q (the region of the NF1 gene) were seen in 9/27 (33%) of MPNSTs. Among nine cases of solitary fibrous tumor (in which previous cytogenetic data are very limited) no consistent aberrations were identified. We conclude that, with the exception of synovial sarcoma, most spindle-cell sarcomas share with pleomorphic sarcomas the tendency for karyotypic complexity. There was no indication (in most of these lesions) that detectable cytogenetic aberrations could either facilitate their diagnosis or help to determine prognosis. There is a clear need to further study and understand the significance of multiple chromosomal abnormalities in this group of mesenchymal neoplasms with the particular goal of determining their role in the process of tumor development. (+info)
The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome.
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Cytogenetically, synovial sarcoma (SS) is characterized by the translocation t(X;18)(p11.2;q11.2), resulting in a fusion between the SYT gene on chromosome 18 and SSX1 or SSX2 on the X chromosome and the formation of new chimeric genes, SYT-SSX1 or SYT-SSX2. We examined the potential clinical relevance of SYT-SSX1 and SYT-SSX2 fusion transcripts together with tumor proliferation. In a series of 33 patients with primary SS, the type of fusion transcript was assessed by reverse transcription-PCR and sequence analysis. The proliferation rate was analyzed using anti-Ki-67 antibodies. One case carrying an atypical transcript with a 57-bp insert was excluded, leaving 13 SYT-SSX1 and 19 SYT-SSX2 cases for analysis. The hazard ratio (with respect to metastasis-free survival for patients with SYT-SSX1 versus patients with SYT-SSX2 fusion transcripts was 7.4 (95% confidence interval, 1.5-36; log-rank P = 0.004). There was also an association with reduced overall survival for patients with SYT-SSX1 compared to patients with SYT-SSX2 (hazard ratio, 8.5; 95% confidence interval, 1.0-73; log-rank P = 0.02). The 5-year metastasis-free survival for patients with SYT-SSX1 was 42% versus 89% for patients with SYT-SSX2. There was a significant association between SYT-SSX1 and a high tumor proliferation rate (P = 0.02). 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. (+info)
Expression of insulin-like growth factor-1 receptor in synovial sarcoma: association with an aggressive phenotype.
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It is well known that insulin-like growth factor-1 receptor (IGF-1R) plays a crucial role in proliferation and survival of transformed cells. Overexpression of IGF-1R in certain tumors has been reported, but there is still little known about its importance in vivo. Here, we evaluated the IGF-1R levels in 35 human synovial sarcoma tumors by Western blot and reverse transcriptase-PCR. In 18 of these, IGF-1R was detectable by Western blot, whereas 17 were nondetectable. There was a significant association between the amount of receptor proteins and mRNA transcripts. Furthermore, we found that the IGF-1R Western blot-positive tumors were associated with a high incidence of lung metastases. Eleven of 18 (61%) developed metastases in the IGF-1R detectable group, compared to 3 of 17 (18%) in the nondetectable group (P = 0.01). Moreover, in the detectable group of IGF-1R, 12 of 18 (67%) exhibited a high tumor cell proliferative rate, compared to 5 of 16 (31%) in the nondetectable group (P = 0.04). On the other hand, no association was found between the IGF-1R and type of fusion gene transcript (SYT-SSX1 or SYT-SSX2). Our results suggest that expression of IGF-1R can underlie an aggressive phenotype in synovial sarcoma. (+info)
Ki-67 is strongly prognostic in synovial sarcoma: analysis based on 86 patients from the Scandinavian Sarcoma group register.
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In a study based on formalin-fixed paraffin-embedded material from 86 patients with primary synovial sarcoma located in the extremities or on the trunk wall, the prognostic importance of MIB-1 index, p53-expession and tumour size was analysed. Multivariate analysis identified two metastatic risk factors: increasing tumour size and MIB-1 > 9%. The 5-year metastasis-free survival-rate for patients with tumour size < or = 5 cm + MIB-1 < 10% was 0.83 (95% confidence interval (CI) 0.64-0.92) compared to 0.31 (95% CI 0.11-0.53) in cases with tumour size > 5 cm + MIB-1 > or = 10%. Our study shows that metastatic disease in synovial sarcoma is closely related to MIB-1 index. Using our model based on tumour size and MIB-1 index, cases with good and poor prognosis can easily be discriminated. Therefore our model can be used to identify patients who should be considered for adjuvant chemotherapy. (+info)
Primary pericardial synovial sarcoma with detection of the chimeric transcript SYT-SSX.
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We report a case of a 19-year-old woman with a primary pericardial synovial sarcoma that extended from the right ventricular free wall to the posterior aspect of the left anterior thoracic wall. Synovial sarcoma was diagnosed by the detection of the chimeric transcript SYT-SSX using reverse transcriptase-polymerase chain reaction (RT-PCR). This transcript is generated by reciprocal translocation between chromosomes X and 18, and is specific to synovial sarcoma that usually occurs in the extremities of young adults. When pathological and immunohistochemical diagnosis of synovial sarcoma is difficult, the molecular biological technique using RT-PCR becomes a powerful method of confirmation of this neoplasm. (+info)
We report a case of synovial sarcoma (SS) showing unusual histology at distant sites. A 47-year-old man was aware of a tumor on the sole of his left foot. After preoperative chemotherapy with a diagnosis of SS, wide excision was performed. During postoperative chemotherapy, multiple tumorous lesions developed in the bone (including the whole spine) and both lungs. The patient died 1 year later. Histologically, the excised tumor of the foot showed a biphasic cellular pattern typical of SS, whereas at autopsy the bone and lung lesions were composed only of undifferentiated small round cells with cytoplasmic fibrillar processes. Homer-Wright rosettes were also observed. Immunohistochemically, 80% of the bone and lung tumor cells expressed MIC2 protein homogeneously. To clarify whether the bone and lung round cell tumors were metastatic lesions or second malignancies, especially primary primitive neuroectodermal tumor (PNET)/Ewing's sarcoma (ES), we performed reverse transcription-polymerase chain reaction (RT-PCR) analysis of tumor type-specific fusion gene transcripts. The SYT/SSX fusion transcript was identified in both the foot and lung lesions, whereas the EWS/FLI1 transcript was not detected in either lesion. Therefore, we concluded that the multiple bone and lung tumors were poorly differentiated metastatic tumors, which arose from the SS of the foot. We also conclude that the identification of chimeric fusion transcripts can be successfully applied to poorly differentiated sarcomas and will help in the differential diagnosis of tumors that cannot be distinguished by conventional morphological examinations. Also, it should be remembered that cytoplasmic staining for MIC2 protein may occur in sarcomas other than PNET/ES. (+info)