SS18

Gene Summary

Gene:SS18; synovial sarcoma translocation, chromosome 18
Aliases: SYT, SSXT
Location:18q11.2
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein SSXT
HPRD
Source:NCBIAccessed: 16 March, 2015

Ontology:

What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Keratins
  • Messenger RNA
  • Amino Acid Sequence
  • Paraffin Embedding
  • Differential Diagnosis
  • Immunohistochemistry
  • DNA, Complementary
  • Synovial Sarcoma
  • Chromosome 18
  • SS18
  • Transcriptional Activation
  • Gene Rearrangement
  • Oncogene Fusion Proteins
  • Two-Hybrid System Techniques
  • RNA Interference
  • Base Sequence
  • Proteins
  • Apoptosis
  • Cancer DNA
  • Transcription
  • Neoplasm Proteins
  • Transcription Factors
  • Cell Proliferation
  • Childhood Cancer
  • Molecular Sequence Data
  • Karyotyping
  • Polymerase Chain Reaction
  • Cell Nucleus
  • Young Adult
  • Repressor Proteins
  • Binding Sites
  • In Situ Hybridization
  • Tissue Array Analysis
  • RTPCR
  • Tumor Antigens
  • Cancer Gene Expression Regulation
  • Proto-Oncogene Proteins
  • FISH
  • SSX1
  • Adolescents
  • Recombinant Fusion Proteins
Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Synovial Sarcomat(X;18)(p11.2;q11.2) SS18-SSX1 in Synovial Sarcoma
A SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is characteristic nearly all synovial sarcomas. This translocation fuses the SS18 (SYT) gene from chromosome 18 to one of three homologous genes at Xp11: SSX1, SSX2 or SSX4.
Synovial Sarcomat(X;18)(p11.2;q11.2) SS18-SSX2 in Synovial Sarcoma
A SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is characteristic nearly all synovial sarcomas. This translocation fuses the SS18 (SYT) gene from chromosome 18 to one of three homologous genes at Xp11: SSX1, SSX2 or SSX4.
Synovial Sarcomat(X;18)(p11.2;q11.2) SS18-SSX4 in Synovial Sarcoma
A SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is characteristic nearly all synovial sarcomas. This translocation fuses the SS18 (SYT) gene from chromosome 18 to one of three homologous genes at Xp11: SSX1, SSX2 or SSX4.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SS18 (cancer-related)

Minami Y, Kohsaka S, Tsuda M, et al.
SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1.
Cancer Sci. 2014; 105(9):1152-9 [PubMed] Related Publications
MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3'-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma.

Wakamatsu T, Naka N, Sasagawa S, et al.
Deflection of vascular endothelial growth factor action by SS18-SSX and composite vascular endothelial growth factor- and chemokine (C-X-C motif) receptor 4-targeted therapy in synovial sarcoma.
Cancer Sci. 2014; 105(9):1124-34 [PubMed] Related Publications
Synovial sarcoma (SS) is a malignant soft-tissue tumor characterized by the recurrent chromosomal translocation SS18-SSX. Vascular endothelial growth factor (VEGF)-targeting anti-angiogenic therapy has been approved for soft-tissue sarcoma, including SS; however, the mechanism underlying the VEGF signal for sarcomagenesis in SS is unclear. Here, we show that SS18-SSX directs the VEGF signal outcome to cellular growth from differentiation. Synovial sarcoma cells secrete large amounts of VEGF under spheroid culture conditions in autocrine fashion. SS18-SSX knockdown altered the VEGF signaling outcome, from proliferation to tubular differentiation, without affecting VEGF secretion, suggesting that VEGF signaling promoted cell growth in the presence of SS18-SSX. Thus, VEGF inhibitors blocked both host angiogenesis and spheroid growth. Simultaneous treatment with VEGF and chemokine (C-X-C motif) (CXC) ligand 12 and CXC receptor 4 inhibitors and/or ifosfamide effectively suppressed tumor growth both in vitro and in vivo. SS18-SSX directs the VEGF signal outcome from endothelial differentiation to spheroid growth, and VEGF and CXC receptor 4 are critical therapeutic targets for SS.

Kimura H, Yamamoto N, Nishida H, et al.
Synovial sarcoma in knee joint, mimicking low-grade sarcoma confirmed by molecular detection of SYT gene split.
Anticancer Res. 2014; 34(6):3105-11 [PubMed] Related Publications
A 10-year-old boy underwent arthroscopic curettage for an intra-articular mass in knee joint. The tumor was diagnosed as low-grade fibrous sarcoma. Five years later, the patient presented with a recurrent tumor. The patient underwent a marginal excision with knee joint preservation and without adjuvant therapy. Two years after the last surgery, the patient is thriving with no evidence of recurrent or metastatic disease. The final diagnosis was synovial sarcoma confirmed via a SYT gene split performed with fluorescent in situ hybridization (FISH), although the tumor appeared as a low-grade fibrous type in a hematoxylin-eosin section. The first curetted specimen was also confirmed to bear a SYT gene split. Synovial sarcoma has been conventionally recognized as a high-grade sarcoma. Our patient had a tumor that exhibited the characteristics of both a histologically and clinically low-grade tumor. From the present case, we consider that low-grade variants of synovial sarcoma do exist although their existence remains controversial.

Silverstein D, Klein P
Large monophasic synovial sarcoma: a case report and review of the literature.
Cutis. 2014; 93(1):13-6 [PubMed] Related Publications
Synovial sarcomas account for approximately 8% of all soft tissue tumors. The hallmark tumor marker is the t(X;18) translocation, which results in fusion of the SYT gene of chromosome 18 to the SSX gene of the X chromosome, creating most frequently either an SYT-SSX1 or SYT-SSX2 transfusion transcript. Clinically, synovial sarcomas most often present on the extremities and average roughly 7 cm in diameter. Metastatic spread to regional lymph nodes and/or the lungs is common. Because the incidence of this tumor is low, most studies have been retrospective; therefore, management and prognostic interpretation has remained controversial. We report a case of a patient who presented with a slowly growing, unusually large mass on the left forearm of 10 years' duration. A diagnosis of monophasic synovial sarcoma was confirmed by biopsy. We also review the literature regarding management strategies for synovial sarcomas.

Clevenger JA, Saxena R, Idrees MT
A de novo unclassified malignant spindle cell neoplasm of liver allograft.
Arch Pathol Lab Med. 2014; 138(2):274-7 [PubMed] Related Publications
Spindle cell neoplasms are rarely reported in liver allografts; most are benign and associated with Epstein-Barr virus infection. We present a case of a malignant spindle cell neoplasm arising in a liver allograft. The patient underwent orthotopic liver transplant for cirrhosis secondary to nonalcoholic steatohepatitis. After 2 years, he presented with vague abdominal complaints. Imaging studies revealed a 10-cm right hepatic lobe mass. The patient underwent right-sided hepatectomy. The tumor displayed areas of broad, relatively hypocellular fascicles, whorls, and perivascular clustering; spindle cells with mild to moderate nuclear pleomorphism; and relatively abundant eosinophilic cytoplasm. Mitotic activity ranged from 2 to 4 mitotic figures per 20 high-power fields. Immunostaining displayed positivity for epithelial membrane antigen, vimentin, CD99, BCL2, cytokeratin, and human herpesvirus 8. Interphase fluorescence in situ hybridization findings were negative for a translocation involving the SS18 gene (18q11). We believe the tumor represents the first reported case of a novel unclassified spindle cell malignant neoplasm in a liver allograft.

Saito T
The SYT-SSX fusion protein and histological epithelial differentiation in synovial sarcoma: relationship with extracellular matrix remodeling.
Int J Clin Exp Pathol. 2013; 6(11):2272-9 [PubMed] Free Access to Full Article Related Publications
Synovial sarcoma (SS) tumor cells, which have the chromosomal translocation t(X;18)(p11.2;q11.2), have an inherently greater propensity for epithelial differentiation than other mesenchymal tumors, especially spindle cell sarcomas. This is caused by de-repression of the transcription of E-cadherin by SYT-SSX1 and SYT-SSX2, which dissociate Snail or Slug, respectively, from the E-cadherin promoter. However, a subset of SS with SYT-SSX1 loses E-cadherin expression despite adequate de-repression because of mutations in E-cadherin, resulting in monophasic histology. The ratio of the expression levels of SYT-SSX1 and Snail is also associated with E-cadherin expression: the lower the SYT-SSX1/Snail ratio, the lower the level of E-cadherin expression, and vice versa, thus affecting tumor histology. In addition, Wnt signal activation caused by mutation of β-catenin, APC, or Axin 1 and 2 is associated with monophasic histology. Remodeling of the extracellular matrix is also important. Only cells that survive all of these steps can finally exhibit biphasic histology. On the other hand, the SYT-SSX2 fusion has a weaker de-repression effect on the E-cadherin promoter than does SYT-SSX1, so it is difficult for SYT-SSX2-expressing tumors to achieve sufficient capacity for epithelial differentiation to form glandular structures. This review provides an interesting model for this epithelial differentiation that shows a possible mechanism for the aberrant mesenchymal to epithelial transition of SS and suggests that it might better be considered an epithelial to mesenchymal transition.

Antonescu C
Round cell sarcomas beyond Ewing: emerging entities.
Histopathology. 2014; 64(1):26-37 [PubMed] Related Publications
Primitive small blue round cell tumours (SBRCT) of childhood and young adults have been problematic to diagnose and classify. Diagnosis is also complicated in cases with atypical morphology, aberrant immunoprofiles and unusual clinical presentations. Even with the increased use of ancillary techniques in archival material, such as immunohistochemistry and molecular/genetic methods, a proportion of these tumours cannot be subclassified into specific histological types. A subset of tumours resembling microscopically the Ewing sarcoma family of tumours (EFT), being composed of primitive small round cells and occurring in paediatric or young adult age groups, remain unclassified, being negative for EWSR1, SS18(SYT), DDIT3(CHOP) and FOXO1(FKHR) gene rearrangements by FISH/RT-PCR. A small number of cases sharing the undifferentiated EFT appearance have been characterized recently carrying BCOR-CCNB3 or CIC-DUX4 fusions. However, based on the somewhat limited number of cases, it remains unclear if these newly defined genetic entities belong to any of the pre-existing clinicopathological disorders or represent altogether novel conditions. This review presents the latest molecular findings related to these SBRCTs, beyond the common EWSR1-ETS fusions. Specific attention has been paid to morphological features not associated typically with classic EFT, and the value of ancillary tests that can be applied when dealing with EWSR1-negative SBRCTs is discussed.

Trautmann M, Sievers E, Aretz S, et al.
SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma.
Oncogene. 2014; 33(42):5006-16 [PubMed] Related Publications
Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/β-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/β-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear β-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/β-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/β-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/β-catenin protein-protein interaction significantly blocked the canonical Wnt/β-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/β-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/β-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.

Yoneda Y, Ito S, Kunisada T, et al.
Truncated SSX protein suppresses synovial sarcoma cell proliferation by inhibiting the localization of SS18-SSX fusion protein.
PLoS One. 2013; 8(10):e77564 [PubMed] Free Access to Full Article Related Publications
Synovial sarcoma is a relatively rare high-grade soft tissue sarcoma that often develops in the limbs of young people and induces the lung and the lymph node metastasis resulting in poor prognosis. In patients with synovial sarcoma, specific chromosomal translocation of t(X; 18) (p11.2;q11.2) is observed, and SS18-SSX fusion protein expressed by this translocation is reported to be associated with pathogenesis. However, role of the fusion protein in the pathogenesis of synovial sarcoma has not yet been completely clarified. In this study, we focused on the localization patterns of SS18-SSX fusion protein. We constructed expression plasmids coding for the full length SS18-SSX, the truncated SS18 moiety (tSS18) and the truncated SSX moiety (tSSX) of SS18-SSX, tagged with fluorescent proteins. These plasmids were transfected in synovial sarcoma SYO-1 cells and we observed the expression of these proteins using a fluorescence microscope. The SS18-SSX fusion protein showed a characteristic speckle pattern in the nucleus. However, when SS18-SSX was co-expressed with tSSX, localization of SS18-SSX changed from speckle patterns to the diffused pattern similar to the localization pattern of tSSX and SSX. Furthermore, cell proliferation and colony formation of synovial sarcoma SYO-1 and YaFuSS cells were suppressed by exogenous tSSX expression. Our results suggest that the characteristic speckle localization pattern of SS18-SSX is strongly involved in the tumorigenesis through the SSX moiety of the SS18-SSX fusion protein. These findings could be applied to further understand the pathogenic mechanisms, and towards the development of molecular targeting approach for synovial sarcoma.

Lee KW, Lee NK, Ham S, et al.
Twist1 is essential in maintaining mesenchymal state and tumor-initiating properties in synovial sarcoma.
Cancer Lett. 2014; 343(1):62-73 [PubMed] Related Publications
Synovial sarcoma is an aggressive mesenchymal tumor with dual differentiation; epithelial and mesenchymal differentiation. However, the molecular mechanisms behind tumorigenesis and dual differentiation have remained elusive. In this study, we investigated whether Twist1 is an essential transcription factor for maintaining tumor-initiating cell properties in synovial sarcoma. First, we identified that Twist1 is overexpressed in most cases of synovial sarcoma (SS) samples as well as in two synovial sarcoma cell lines (HSSYII, SW982). Additionally, Twist1 depletion led to down-regulation of mesenchymal markers and up-regulation of epithelial markers in SS cell lines. The migratory and invasive abilities of SS cell lines were also significantly reduced following the loss of Twist1. These results indicate that Twist1 plays an essential role in the maintenance of mesenchymal character in SS. Furthermore, knock-down of Twist1 induced G1 cycle arrest and apoptosis as well as remarkable reduction in the sphere-forming cell subpopulation and side population cells. Moreover, Twist1 knock-down profoundly inhibited the growth of synovial sarcoma xenograft in nude mice compared to controls indicating that Twist1 is essential for tumor initiating cell properties. To explore transcriptional regulation by Twist1 at the genomic level, Chromatin immunoprecipiation-solexa whole genome sequencing (ChIP-SEQ) and cDNA microarray analysis were performed. Mesenchymal differentiation/proliferation and PDGF related genes were found to be affected by Twist1. Finally, depletion of SS18-SSX fusion oncoprotein by RNA inference induced down-regulation of Twist1, implying that Twist1 is regulated by SS18-SSX. Hence, our results suggest that Twist1 is an essential transcription factor for the maintenance of mesenchymal characters and tumor initiating properties of synovial sarcoma.

Ren T, Lu Q, Guo W, et al.
The clinical implication of SS18-SSX fusion gene in synovial sarcoma.
Br J Cancer. 2013; 109(8):2279-85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of this study is to evaluate distribution and clinical impact of the SS18-SSX fusion gene in patients with synovial sarcoma in China.
METHODS: We collected and analysed the clinical data of 88 patients using univariate and multivariate survival analysis. HEK 293T and NIH 3T3 cell lines were transfected with the SS18-SSX1 or SS18-SSX2 gene to determine the respective involvement of these fusion genes in cell proliferation and invasion.
RESULTS: Overall survival was significantly better among SS18-SSX2 cases (P=0.001), FNCLCC grade 2 cases (P<0.001), and UICC stage 1 or 2 (P<0.001) by univariate and multivariate survival analysis. SS18-SSX1-positive cells were more proliferative and invasive than SS18-SSX2-positive cells.
CONCLUSION: SS18-SSX fusion type is a significant prognostic factor for patients with synovial sarcoma.

Barham W, Frump AL, Sherrill TP, et al.
Targeting the Wnt pathway in synovial sarcoma models.
Cancer Discov. 2013; 3(11):1286-301 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. 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.
SIGNIFICANCE: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans.

Sahara S, Otsuki Y, Egawa Y, et al.
Primary synovial sarcoma of the stomach--a case report and review of the literature.
Pathol Res Pract. 2013; 209(11):745-50 [PubMed] Related Publications
Synovial sarcoma (SS) is a mesenchymal spindle cell tumor which displays variable epithelial differentiation. It commonly arises around the major joints or tendon sheaths in young adults, but is not commonly seen in the stomach. We experienced a case of primary gastric SS. The patient is a 22-year-old male, who presented with epigastric pain. Upper endoscopy showed an ulcer of 25 mm in diameter with marginal elevation on the posterior mid-gastric body. Biopsy of the ulcer base showed monotonous proliferation of small spindle-shaped cells on HE-stain. On immunohistochemical staining, these cells were positively stained with vimentin, cytokeratin, epithelial membrane antigen, and CD99, but were negative for KIT, CD34, desmin, and S-100 protein. These findings were compatible with SS of monophasic type. Diagnosis of primary gastric SS was made because there were no other primary lesions, nor metastatic lesions. The wedge resection was performed. Reverse transcriptase polymerase chain reaction (RT-PCR), using the RNA from frozen neoplastic tissue of the resected specimen, detected a fusion gene called SYT-SSX1, specific for SS. Though SS arising in the stomach is rare, it should be considered in the differential diagnosis of KIT-negative gastric spindle cell tumor.

Choi EY, Thomas DG, McHugh JB, et al.
Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology.
Am J Surg Pathol. 2013; 37(9):1379-86 [PubMed] Related Publications
A subset of small round cell sarcomas remains difficult to classify. Among these, a rare tumor harboring a t(4;19)(q35;q13.1) with CIC-DUX4 fusion has been described. The aim of this study is to better understand its clinicopathologic features. Four cases of CIC-DUX4 sarcoma, all arising in adults (3 women, 1 man, aged 20 to 43 y), were identified using conventional cytogenetic, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methods. All 4 tumors demonstrated CIC-DUX4 fusion transcript by both RT-PCR and FISH and CIC rearrangement by FISH. Cytogenetic results from 2 tumors showed t(4;19)(q35;q13.1) occurring as part of a simple karyotype in 1 tumor and as part of a complex karyotype in the other, the latter from a postchemotherapy specimen. Both tumors harbored trisomy 8 and lacked any other known sarcoma-associated translocation. No EWS or SYT rearrangements were detected by RT-PCR or FISH. The tumors had small round cell morphology with a distinctive constellation of histologic features including extensive geographic necrosis, mild nuclear pleomorphism with coarse chromatin and prominent nucleoli, clear cell areas, and focal myxoid matrix. Only focal staining for CD99 was present in each tumor. Two had very focal cytokeratin staining. All tumors were negative for desmin, myogenin, TLE-1, and S100 protein, whereas nuclear INI-1 staining was retained. The tumors were highly aggressive, and all patients died of disseminated disease within 16.8 months. CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression.

Xiong B, Chen M, Ye F, et al.
Primary monophasic synovial sarcoma of the liver in a 13-year-old boy.
Pediatr Dev Pathol. 2013 Sep-Oct; 16(5):353-6 [PubMed] Related Publications
Synovial sarcoma originating in the liver is extremely rare, and thus far only 3 cases have been reported in the English literature. Herein, we report a primary hepatic synovial sarcoma in a 13-year-old Chinese boy. This patient present with a 10-day right upper quadrant pain, and a heterogeneous mass was documented in the right hepatic lobe by computed tomography. Subsequently, the patient underwent right hepatectomy. Histologically, the tumor exhibited classic features of monophasic synovial sarcoma. The diagnosis was confirmed by the presence of SS18 gene rearrangement and identification of SS18-SSX1 fusion transcript. Unfortunately, a relapsing mass was detected 11 months after the surgery. To the best of our knowledge, the current case is the 1st published example in the pediatric population.

Ichimura H, Kikuchi S, Ozawa Y, Matsuzaki K
Primary synovial sarcoma of the lung successfully resected under temporary bypass.
Interact Cardiovasc Thorac Surg. 2013; 17(3):588-90 [PubMed] Free Access to Full Article Related Publications
A 48-year old man presented with chest pain and haemoptysis. Chest computed tomography showed a 60-mm mass in the left upper lobe of the lung, adjacent to the distal aortic arch. Bronchoscopic cytology revealed the presence of malignant cells and, in the absence of evidence of distant metastasis, a thoracotomy was performed. Although the tumour was firmly adherent to the distal aortic arch, under temporary bypass from the left subclavian artery to the descending aorta, it was successfully resected en bloc with the section of the aorta attached to it. The tumour was diagnosed as a primary synovial sarcoma of the lung on the basis of histopathological findings and fluorescent chromogenic in situ hybridization, showing SS18 gene rearrangement.

Carmody Soni EE, Schlottman S, Erkizan HV, et al.
Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma.
Clin Orthop Relat Res. 2014; 472(3):874-82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Most synovial sarcomas contain a chromosomal translocation t(X;18), which results in the formation of an oncoprotein SS18-SSX critical to the viability of synovial sarcoma.
QUESTIONS/PURPOSES: We (1) established and characterized three novel synovial sarcoma cell lines and asked (2) whether inhibition of SS18-SSX1 decreases cell viability in these cell lines; and (3) whether reduction in viability after SS18-SSX1 knockdown is caused by apoptosis. After identifying a specific posttranscriptional splice variant in our cell lines, we asked (4) whether this provides a survival benefit in synovial sarcoma.
METHODS: Cells lines were characterized. SS18-SSX1 knockdown was achieved using a shRNA system. Cell viability was assessed by WST-1 analysis and apoptosis examined by caspase-3 activity.
RESULTS: We confirmed the SS18-SSX1 translocation in all cell lines and identified a consistent splicing variant. We achieved successful knockdown of SS18-SSX1 and with this saw a significant reduction in cell viability. Decreased viability was a result of increased apoptosis. Reintroduction of the exon 8 sequence into cells reduced cell viability in all cell lines.
CONCLUSIONS: We confirmed the presence of the SS18-SSX1 translocation in our cell lines and its importance in the survival of synovial sarcoma. We have also demonstrated that reduction in cell viability is related to an increase in apoptosis. In addition, we have identified a potential mediator of SS18-SSX function in exon 8.
CLINICAL RELEVANCE: SS18-SSX represents a tumor-specific target in synovial sarcoma. Exploitation of SS18-SSX and its protein partners will allow us to develop potent tumor-specific therapeutic agents.

Yin L, Chen M, Ye F, et al.
A poorly differentiated synovial sarcoma arising from the pulmonary valve.
Cardiovasc Pathol. 2013 Nov-Dec; 22(6):501-2 [PubMed] Related Publications
Synovial sarcoma originating in the pulmonary valve is extremely rare. Herein, we report a poorly differentiated synovial sarcoma arising from this peculiar location in a 17-year-old Chinese boy. Histologically, this tumor was entirely poorly differentiated with uniform small round cell morphology, and it exhibited prominent myxoid change in some areas. The diagnosis was confirmed by the presence of SS18 rearrangement and identification of the SS18-SSX1 fusion transcript. To the best of our knowledge, the present case is the first published example of synovial sarcoma occurring in the pulmonary valve. Additionally, this is the first case showing entirely uniform small round cell morphology without classic areas of synovial sarcoma.

Kadoch C, Hargreaves DC, Hodges C, et al.
Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy.
Nat Genet. 2013; 45(6):592-601 [PubMed] Free Access to Full Article Related Publications
Subunits of mammalian SWI/SNF (mSWI/SNF or BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of endogenous mSWI/SNF complexes, which identified several new dedicated, stable subunits not found in yeast SWI/SNF complexes, including BCL7A, BCL7B and BCL7C, BCL11A and BCL11B, BRD9 and SS18. Incorporating these new members, we determined mSWI/SNF subunit mutation frequency in exome and whole-genome sequencing studies of primary human tumors. Notably, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, mutations affecting more than one subunit, defined here as compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53. Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression.

Kadoch C, Crabtree GR
Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma.
Cell. 2013; 153(1):71-85 [PubMed] Free Access to Full Article Related Publications
Recent exon sequencing studies have revealed that over 20% of human tumors have mutations in subunits of mSWI/SNF (BAF) complexes. To investigate the underlying mechanism, we studied human synovial sarcoma (SS), in which transformation results from the translocation of exactly 78 amino acids of SSX to the SS18 subunit of BAF complexes. We demonstrate that the SS18-SSX fusion protein competes for assembly with wild-type SS18, forming an altered complex lacking the tumor suppressor BAF47 (hSNF5). The altered complex binds the Sox2 locus and reverses polycomb-mediated repression, resulting in Sox2 activation. Sox2 is uniformly expressed in SS tumors and is essential for proliferation. Increasing the concentration of wild-type SS18 leads to reassembly of wild-type complexes retargeted away from the Sox2 locus, polycomb-mediated repression of Sox2, and cessation of proliferation. This mechanism of transformation depends on only two amino acids of SSX, providing a potential foundation for therapeutic intervention.

van Hemel BM, Suurmeijer AJ
Effective application of the methanol-based PreservCyt(™) fixative and the Cellient(™) automated cell block processor to diagnostic cytopathology, immunocytochemistry, and molecular biology.
Diagn Cytopathol. 2013; 41(8):734-41 [PubMed] Related Publications
We studied the feasibility of immunocytochemistry (ICC), in situ hybridization (ISH), and polymerase chain reaction (PCR) after Cellient(™) automated cell block processing, and tested whether methanol-based PreservCyt(™) fixation could replace formalin fixation, in an attempt to eliminate toxic formaldehyde vapors. Immunostaining with 30 different antibodies was performed on cell blocks from 73 FNA specimens and 42 body cavity fluid specimens prepared by Cellient(™) automated processing that uses the methanol-based fixative (PreservCyt(™) ). For each antibody we evaluated ICC in at least three different cell block specimens and compared it with immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded (FFPE) histological sections from the corresponding tumors. The quality of DNA and RNA in Cellient(™) blocks was analyzed by ISH, applying a SYT gene break-apart assay and EBER probes, respectively. Moreover, DNA quality was analyzed by PCR by using primer sets for DNA products of 100, 200, 300, 400, 500, and 600 base pairs, and evaluated by gel electrophoresis. When compared with IHC results in corresponding FFPE tumor tissue from the same patient, 24 out of 30 antibodies showed concordant ICC results. With FISH, distinctive hybridization signals were observed for SYT DNA sequences and EB virus RNA sequences. With PCR, DNA products, up to 600 base pairs in size, were readily observed after gel electrophoresis. The antibodies that showed concordant immunostaining in Cellient(™) blocks could be applied to diagnostic algorithms that proved to be helpful in the discrimination of major tumor types (carcinoma, lymphoma, melanoma, and germ cell tumors), discrimination of carcinoma subtypes, and determination of primary tumor site in cases of metastatic carcinoma. In a separate study, we found that the application of ICC to this cell block technique provided additional diagnostic and clinically important information in 24% of 100 consecutive cases. The high quality of DNA and RNA in Cellient(™) cell blocks allowed sensitive and specific molecular biologic analysis, in particular FISH and PCR.

Hayakawa K, Ikeya M, Fukuta M, et al.
Identification of target genes of synovial sarcoma-associated fusion oncoprotein using human pluripotent stem cells.
Biochem Biophys Res Commun. 2013; 432(4):713-9 [PubMed] Related Publications
Synovial sarcoma (SS) is a malignant soft tissue tumor harboring chromosomal translocation t(X; 18)(p11.2; q11.2), which produces SS-specific fusion gene, SYT-SSX. Although precise function of SYT-SSX remains to be investigated, accumulating evidences suggest its role in gene regulation via epigenetic mechanisms, and the product of SYT-SSX target genes may serve as biomarkers of SS. Lack of knowledge about the cell-of-origin of SS, however, has placed obstacle in the way of target identification. Here we report a novel approach to identify SYT-SSX2 target genes using human pluripotent stem cells (hPSCs) containing a doxycycline-inducible SYT-SSX2 gene. SYT-SSX2 was efficiently induced both at mRNA and protein levels within three hours after doxycycline administration, while no morphological change of hPSCs was observed until 24h. Serial microarray analyses identified genes of which the expression level changed more than twofold within 24h. Surprisingly, the majority (297/312, 95.2%) were up-regulated genes and a result inconsistent with the current concept of SYT-SSX as a transcriptional repressor. Comparing these genes with SS-related genes which were selected by a series of in silico analyses, 49 and 2 genes were finally identified as candidates of up- and down-regulated target of SYT-SSX, respectively. Association of these genes with SYT-SSX in SS cells was confirmed by knockdown experiments. Expression profiles of SS-related genes in hPSCs and human mesenchymal stem cells (hMSCs) were strikingly different in response to the induction of SYT-SSX, and more than half of SYT-SSX target genes in hPSCs were not induced in hMSCs. These results suggest the importance of cellular context for correct understanding of SYT-SSX function, and demonstrated how our new system will help to overcome this issue.

Salcedo-Hernández RA, Lino-Silva LS, Luna-Ortiz K
Synovial sarcomas of the head and neck: comparative analysis with synovial sarcoma of the extremities.
Auris Nasus Larynx. 2013; 40(5):476-80 [PubMed] Related Publications
OBJECTIVE: This study analyzed synovial sarcoma (SS) of the head and neck in order to identify features associated with survival improvement and compared them with the survival of SS of limbs.
METHODS: Clinical charts and histopathologic material with analysis for SYT/SSX gene rearrangement of 16 patients were reviewed. The clinicopathologic features and their association with survival were analyzed and compared with 174 SS of limbs.
RESULTS: The average age was 24.2 years (range 21-86). Eight cases occurred in each sex. The most frequent site was the parapharyngeal space (PPS). The mean tumor size was 5.38cm. Sixty-nine percent occurred in Stages II-III and 9% in Stage IV. Fifteen cases were excised: R0 resection in seven (46.7%) cases and R1 resection in eight (53.3%) cases. No patient with R0 resection has recurred, and three patients (37.5%) with R1 resection have recurred (p=0.035). Patients with R0 surgery had better survival rates compared to those who received other treatments (p=0.045). SS of head and neck showed a 5-year survival rate of 58% compared to 44.6% of the limbs (p=0.450).
CONCLUSION: The most prevalent location was the PPS. Surgical resection with clear margins correlated with low recurrence. Head and neck sarcomas had similar survival rates compared to sarcomas of limbs.

Valente AL, Tull J, Zhang S
Specificity of TLE1 expression in unclassified high-grade sarcomas for the diagnosis of synovial sarcoma.
Appl Immunohistochem Mol Morphol. 2013; 21(5):408-13 [PubMed] Related Publications
Expression of the transducin-like enhancer of split 1 (TLE1) by immunohistochemistry (IHC) has been widely used as a biomarker for the diagnosis of synovial sarcoma. Although TLE1 expression can be identified in more than 90% of synovial sarcomas, positive staining has been reported in up to one third of nonsynovial sarcomas, including peripheral nerve sheath tumors and neoplasms of fibrous and adipose tissues. The low specificity of this test in soft tissue tumors raises concern on its clinical application as a diagnostic biomarker. As synovial sarcoma is frequent among the differential diagnosis of unclassified high-grade sarcomas, and considering that the specificity of TLE1 antibody in this tumor group remains unclear, we evaluated TLE1 expression by IHC in 42 unclassified high-grade sarcomas. SS18 (SYT) gene break-apart analyses by fluorescence in situ hybridization were simultaneously performed as a gold standard biomarker for synovial sarcoma. Five cases that were positive for the SS18 break-apart by fluorescence in situ hybridization were also positive for TLE1 by IHC, whereas the remaining 37 cases negative for SS18 break-apart were all negative for TLE1. The results showed no evidence of nonspecific TLE1 expression in the nonsynovial high-grade sarcomas. We concluded that TLE1 is a highly specific biomarker for synovial sarcoma in the setting of differential diagnosis of unclassified high-grade sarcomas.

Changchien YC, Tátrai P, Papp G, et al.
Poorly differentiated synovial sarcoma is associated with high expression of enhancer of zeste homologue 2 (EZH2).
J Transl Med. 2012; 10:216 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a polycomb group (PcG) family protein. Acting as a histone methyltransferase it plays crucial roles in maintaining epigenetic stem cell signature, while its deregulation leads to tumor development. EZH2 overexpression is commonly associated with poor prognosis in a variety of tumor types including carcinomas, lymphomas and soft tissue sarcomas. However, although the synovial sarcoma fusion proteins SYT-SSX1/2/4 are known to interact with PcG members, the diagnostic and prognostic significance of EZH2 expression in synovial sarcoma has not yet been investigated. Also, literature data are equivocal on the correlation between EZH2 expression and the abundance of trimethylated histone 3 lysine 27 (H3K27me3) motifs in tumors.
METHODS: Immunohistochemical stains of EZH2, H3K27me3, and Ki-67 were performed on tissue microarrays containing cores from 6 poorly differentiated, 39 monophasic and 10 biphasic synovial sarcomas, and evaluated by pre-established scoring criteria. Results of the three immunostainings were compared, and differences were sought between the histological subtypes as well as patient groups defined by gender, age, tumor location, the presence of distant metastasis, and the type of fusion gene. The relationship between EZH2 expression and survival was plotted on a Kaplan-Meier curve.
RESULTS: High expression of EZH2 mRNA and protein was specifically detected in the poorly differentiated subtype. EZH2 scores were found to correlate with those of Ki-67 and H3K27me3. Cases with high EZH2 score were characterized by larger tumor size (≥ 5cm), distant metastasis, and poor prognosis. Even in the monophasic and biphasic subtypes, higher expression of EZH2 was associated with higher proliferation rate, larger tumor size, and the risk of developing distant metastasis. In these histological groups, EZH2 was superior to Ki-67 in predicting metastatic disease.
CONCLUSIONS: High expression of EZH2 helps to distinguish poorly differentiated synovial sarcoma from the monophasic and biphasic subtypes, and it is associated with unfavorable clinical outcome. Importantly, high EZH2 expression is predictive of developing distant metastasis even in the better-differentiated subtypes. EZH2 overexpression in synovial sarcoma is correlated with high H3K27 trimethylation. Thus, along with other epigenetic regulators, EZH2 may be a future therapeutic target.

Przybyl J, Sciot R, Rutkowski P, et al.
Recurrent and novel SS18-SSX fusion transcripts in synovial sarcoma: description of three new cases.
Tumour Biol. 2012; 33(6):2245-53 [PubMed] Free Access to Full Article Related Publications
Synovial sarcoma (SS) is an aggressive type of tumor, comprising approximately 10 % of soft tissue sarcomas. Over 90 % of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of oncogenic SS18-SSX1 or SS18-SSX2 fusions. In a typical SS18-SSX fusion transcript, exon 10 of SS18 is fused to exon 6 of SSX1/2. However, several variant fusion transcripts have been already described. In the present study, we examined the fusion transcript type in a series of 40 primary untreated SS tumor specimens using reverse transcription polymerase chain reaction and fluorescence in situ hybridization assay. We detected SS18-SSX1 transcript in 22 (55 %) patients and SS18-SSX2 transcript in 17 (42.5 %) patients, while in one patient, none of SS18-SSX1/2 fusion transcripts were identified. Among the cases under study, two tumors carried novel SS18-SSX1 and SS18-SSX2 variant translocations that were allegedly created by an alternative splicing, and in additional case, an unusual translocation variant previously described by other group was found. Our data suggest that alternative splicing may play an important role in novel fusion transcript formation, and additionally we show that it may be a recurrent event in SS. Furthermore, we describe the first case of a complex rearrangement possibly linking SS to REPS2 gene.

Kubouchi Y, Taniguchi Y, Matsuoka Y, et al.
Radiation-induced synovial sarcoma of the lung diagnosed by gene analysis after the surgical resection of chondrosarcoma arising from the scapula.
Ann Thorac Cardiovasc Surg. 2013; 19(2):144-7 [PubMed] Related Publications
The patient was a 62-year-old male who underwent wide resection and radiotherapy for right scapular chondrosarcoma 12 years ago. An abnormal shadow was detected in the right upper lung field included in the irradiated field on chest X-ray. Since the nodule tended to enlarge, a malignant lung tumor was suspected, and surgery was performed. On histological examination, spindle cells densely proliferated in a bundle pattern. Vimentin, bcl-2 protein, and CD99 were positive, and CD34, cytokeratin, AE1/AE3, and EMA were partially positive on immunohistochemical staining. The SYT-SSX (synaptotagmin- synovial sarcoma X) fusion gene was detected employing RT-PCR, based on which primary synovial sarcoma of the lung was diagnosed. The findings also matched the diagnostic criteria of radiation-induced sarcoma, suggesting radiation-induced primary synovial sarcoma of the lung. Primary synovial sarcoma of the lung is a rare tumor. It is difficult to diagnose based on cellular findings, and immunohistochemical and genetic investigations are essential. Radiation-induced sarcoma may develop through a long-term course, as seen in this patient, for which long-term follow-up after radiotherapy is important.

Zhu M, Li J, Wang KJ, Shang JB
Primary synovial sarcoma of the parapharyngeal space: a clinicopathologic study of five cases.
World J Surg Oncol. 2012; 10:158 [PubMed] Free Access to Full Article Related Publications
We report five cases of primary synovial sarcomas arising in the parapharyngeal space. The patients were all men with a median age of 35 years (range 22 to 41 years). The tumors were non-encapsulated solid masses ranging from 2.0 to 6.6 cm in size. Histologically, three cases were biphasic subtype, and the other two cases were monophasic subtype. Immunohistochemically, the tumor cells were strongly positive for bcl-2 and CD99, partly positive for CK and EMA, and negative for CD117, CD34, SMA and desmin in all five cases. S-100 protein was detected in one case. The presence of an SYT-SSX1 and/or SYT-SSX2 gene fusion resulting from t(X;18) was demonstrated from paraffin blocks by reverse transcriptase polymerase chain reaction in five cases. All five patients received tumor radical excision and postoperative radiotherapy, and two patients with pulmonary metastasis received additional chemotherapy. Follow-up data revealed that two patients with tumor size <5 cm were alive without disease for 54 and 57 months, one patient with tumor size <5 cm was alive with pulmonary metastasis for 78 months, and two patients with tumor size >5 cm died of disease 26 and 37 months after the diagnosis, respectively. Primary parapharyngeal synovial sarcoma is a rare variant that occurs more frequently in males than females. Accurate diagnosis depends on morphologic and immunohistochemical examination and proper molecular analysis. The prognosis is relatively good in those patients whose tumor size is less than 5 cm.

Jones KB, Su L, Jin H, et al.
SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.
Oncogene. 2013; 32(18):2365-71, 2375.e1-5 [PubMed] Free Access to Full Article Related Publications
Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through activating transcription factor 2 (ATF2) to the cyclic adenosine monophosphate (AMP) response element (CRE) in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more than the other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.

Ho AL, Vasudeva SD, Laé M, et al.
PDGF receptor alpha is an alternative mediator of rapamycin-induced Akt activation: implications for combination targeted therapy of synovial sarcoma.
Cancer Res. 2012; 72(17):4515-25 [PubMed] Free Access to Full Article Related Publications
Akt activation by the IGF-1 receptor (IGF-1R) has been posited to be a mechanism of intrinsic resistance to mTORC1 inhibitors (rapalogues) for sarcomas. Here we show that rapamycin-induced phosphorylation of Akt can occur in an IGF-1R-independent manner. Analysis of synovial sarcoma cell lines showed that either IGF-1R or the PDGF receptor alpha (PDGFRA) can mediate intrinsic resistance to rapamycin. Repressing expression of PDGFRA or inhibiting its kinase activity in synovial sarcoma cells blocked rapamycin-induced phosphorylation of Akt and decreased tumor cell viability. Expression profiling of clinical tumor samples revealed that PDGFRA was the most highly expressed kinase gene among several sarcoma disease subtypes, suggesting that PDGFRA may be uniquely significant for synovial sarcomas. Tumor biopsy analyses from a synovial sarcoma patient treated with the mTORC1 inhibitor everolimus and PDGFRA inhibitor imatinib mesylate confirmed that this drug combination can impact both mTORC1 and Akt signals in vivo. Together, our findings define mechanistic variations in the intrinsic resistance of synovial sarcomas to rapamycin and suggest therapeutic strategies to address them.

Crew AJ, Clark J, Fisher C, et al.
Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma.
EMBO J. 1995; 14(10):2333-40 [PubMed] Free Access to Full Article Related Publications
We demonstrate that the cytogenetically defined translocation t(X;18)(p11.2;q11.2) found in human synovial sarcoma results in the fusion of the chromosome 18 SYT gene to either of two distinct genes, SSX1 or SSX2, at Xp11.2. The SSX1 and SSX2 genes encode closely related proteins (81% identity) of 188 amino acids that are rich in charged amino acids. The N-terminal portion of each SSX protein exhibits homology to the Kruppel-associated box (KRAB), a transcriptional repressor domain previously found only in Kruppel-type zinc finger proteins. PCR analysis demonstrates the presence of SYT-SSX1 or SYT-SSX2 fusion transcripts in 29 of 32 of the synovial sarcomas examined, indicating that the detection of these hybrid transcripts by PCR may represent a very useful diagnostic method. Sequence analysis has demonstrated heterogeneity in the fusion transcripts with the formation of two distinct SYT-SSX1 fusion junctions and two distinct SYT-SSX2 fusion junctions.

de Leeuw B, Balemans M, Olde Weghuis D, Geurts van Kessel A
Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas.
Hum Mol Genet. 1995; 4(6):1097-9 [PubMed] Related Publications

Kawai A, Woodruff J, Healey JH, et al.
SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma.
N Engl J Med. 1998; 338(3):153-60 [PubMed] Related Publications
BACKGROUND: Synovial sarcomas account for up to 10 percent of soft-tissue sarcomas and include two major histologic subtypes, biphasic and monophasic, defined respectively by the presence and absence of glandular epithelial differentiation in a background of spindle tumor cells. A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. The translocation fuses the SYT gene from chromosome 18 to either of two highly homologous genes at Xp11, SSX1 or SSX2. SYT-SSX1 and SYT-SSX2 are thought to tunction as aberrant transcriptional regulators. We attempted to determine the influence of the two alternative forms of the SYT-SSX fusion gene on tumor morphology and clinical outcome in patients with this sarcoma.
METHODS: We analyzed SYT-SSX fusion transcripts in 45 synovial sarcomas (33 monophasic and 12 biphasic) by the reverse-transcriptase polymerase chain reaction and compared the results with relevant clinical and pathological data.
RESULTS: The SYT-SSX1 and SYT-SSX2 fusion transcripts were detected in 29 (64 percent) and 16 (36 percent) of the tumors, respectively. 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. Kaplan-Meier analysis of 39 patients with localized tumors showed that the 15 patients with SYT-SSX2 had significantly better metastasis-free survival than the 24 patients with SYT-SSX1 (P=0.03 by multivariate analysis; relative risk, 3.0). There were no significant correlations between the type of SYT-SSX transcript and age, sex, tumor location and size, whether there were metastases at diagnosis, or whether patients underwent chemotherapy. Histologic subtype alone was not prognostically important.
CONCLUSIONS: The type of SYT-SSX fusion transcript correlates with both the histologic subtype and the clinical behavior of synovial sarcoma. SYT-SSX fusion transcripts are a defining diagnostic marker of synovial sarcomas and may also yield important independent prognostic information.

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