Research IndicatorsGraph generated 17 March 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 17 March, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (1)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
|Synovial Sarcoma||t(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.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Atlas of Genetics and Cytogenetics in Oncology and Haematology SSX1 gene
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
TICdb, Universidad de Navarra
Search the database of Translocation breakpoints In Cancer for "SSX1"
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: SSX1 (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.
He L, Ji JN, Liu SQ, et al.Expression of cancer-testis antigen in multiple myeloma.
J Huazhong Univ Sci Technolog Med Sci. 2014; 34(2):181-5 [PubMed
] Related Publications
Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen (CTA) has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new approach for multiple myeloma (MM) immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow (BM) cells of 25 MM patients and 18 healthy volunteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% (7/25), 80% (20/25), 40% (10/25) and 68% (17/25), respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% (20/25) MM patients, and that of at least one CTA in 88% (22/25). The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II (P<0.05). No statistically significant differences were observed in the mRNA expression levels of MAGE-C1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM (P>0.05). In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immunotherapy in the future.
Silverstein D, Klein PLarge 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.
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.
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.
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.
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.
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.
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.
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.
Neumann F, Kaddu-Mulindwa D, Widmann T, et al.EBV-transformed lymphoblastoid cell lines as vaccines against cancer testis antigen-positive tumors.
Cancer Immunol Immunother. 2013; 62(7):1211-22 [PubMed
] Related Publications
EBV-transformed lymphoblastoid cell lines (LCL) are potent antigen-presenting cells. To investigate their potential use as cancer testis antigen (CTA) vaccines, we studied the expression of 12 cancer testis (CT) genes in 20 LCL by RT-PCR. The most frequently expressed CT genes were SSX4 (50 %), followed by GAGE (45 %), SSX1 (40 %), MAGE-A3 and SSX2 (25 %), SCP1, HOM-TES-85, MAGE-C1, and MAGE-C2 (15 %). NY-ESO-1 and MAGE-A4 were found in 1/20 LCL and BORIS was not detected at all. Fifteen of 20 LCL expressed at least one antigen, 9 LCL expressed ≥2 CT genes, and 7 of the 20 LCL expressed ≥4 CT genes. The expression of CT genes did not correlate with the length of in vitro culture, telomerase activity, aneuploidy, or proliferation state. While spontaneous expression of CT genes determined by real-time PCR and Western blot was rather weak in most LCL, treatment with DNA methyltransferase 1 inhibitor alone or in combination with histone deacetylase inhibitors increased CTA expression considerably thus enabling LCL to induce CTA-specific T cell responses. The stability of the CT gene expression over prolonged culture periods makes LCL attractive candidates for CT vaccines both in hematological neoplasias and solid tumors.
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.
Qin Y, Deng W, Ekmekcioglu S, Grimm EAIdentification of unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma by a large-scale synthetic lethal RNAi screening.
Pigment Cell Melanoma Res. 2013; 26(1):97-112 [PubMed
] Free Access to Full Article Related Publications
CDDO-Me has been shown to exert potent anti-inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO-Me response in melanoma, we utilized a large-scale synthetic lethal RNAi screen targeting 6000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO-Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P < 0.001). These five genes were then individually validated as targets to potentiate CDDO-Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival and could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma growth control.
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.
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.
Lai JP, Robbins PF, Raffeld M, et al.NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis.
Mod Pathol. 2012; 25(6):854-8 [PubMed
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A promising targeted therapy against NY-ESO-1 (CTAG 1B) using genetically modified T-cells in synovial sarcomas was recently demonstrated in a clinical trial at the NCI. To investigate the role of NY-ESO-1 immunohistochemistry in patient selection and gain better insight into the incidence of NY-ESO-1 expression in synovial sarcomas and other mesenchymal tumors, we evaluated NY-ESO-1 expression by immunohistochemistry in 417 tumors. This collection of samples included: 50 SS18/SSX1/2 fusion positive synovial sarcomas, 155 gastrointestinal stromal tumors (GIST), 135 other spindle cell sarcomas as well as 77 other sarcomas (chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, angiosarcoma, malignant mesothelioma, and Ewing's sarcoma). We report that 76% of synovial sarcomas expressed NY-ESO-1 in a strong and diffuse pattern (2-3+, >50-70% of tumor cells). In contrast, only rare cases of other spindle cell mesenchymal tumor expressed NY-ESO-1 (GIST (2/155), malignant peripheral nerve sheath tumors (1/34), and dermatofibrosarcoma protuberans (2/20)). Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewing's sarcoma) were positive for NY-ESO-1. However, no positive cases were identified amongst our cohort of leiomyosarcomas (0/24), hemangiopericytoma/solitary fibrous tumors (0/40), and cellular schwannomas (0/17). In summary, we find that NY-ESO-1 is strongly and diffusely expressed in a majority of synovial sarcomas, but only rarely in other mesenchymal lesions. Beyond its role in patient selection for targeted therapy, immunohistochemistry for NY-ESO-1 may be diagnostically useful for the distinction of synovial sarcoma from other spindle cell neoplasms.
Setsu N, Kohashi K, Endo M, et al.Inhibin-α and synaptophysin immunoreactivity in synovial sarcoma with granular cell features.
Hum Pathol. 2012; 43(6):850-7 [PubMed
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We recognized immunoreactivity for the α subset of inhibin and synaptophysin in synovial sarcomas with granular cell features. Histologic findings of 90 cases of synovial sarcoma were reviewed. Two (2.2%) of the 90 cases had granular cell features, showing sheet or nested proliferation of characteristic epithelioid cells with abundant eosinophilic and granular cytoplasm, in addition to the typical spindle cell component. The 2 cases were both female (aged 86 and 76 years). The tumors were located in the foot and the retroperitoneum and measured 3.5 and 14 cm in maximum diameter. Reverse transcriptase polymerase chain reaction analysis revealed SS18-SSX1 transcripts in both cases. SS18 gene rearrangement was detected in granular cells as well as spindle cells by chromogenic in situ hybridization. Immunohistochemistry found the granular cells to be positive for inhibin-α in both cases and for synaptophysin in 1 case, whereas spindle cells were not. Thirty-six cases (20 monophasic fibrous, 11 biphasic, and 5 poorly differentiated synovial sarcomas) were additionally examined for comparison; they showed no immunoreactivity for inhibin-α or synaptophysin. This is the first report of immunoreactivity for inhibin-α and synaptophysin in synovial sarcoma. These immunohistochemical findings might be characteristic of synovial sarcomas with granular cell features.
Smith HA, Cronk RJ, Lang JM, McNeel DGExpression and immunotherapeutic targeting of the SSX family of cancer-testis antigens in prostate cancer.
Cancer Res. 2011; 71(21):6785-95 [PubMed
] Related Publications
Recent U.S. Food and Drug Administration approval of the first immunotherapy for prostate cancer encourages efforts to improve immune targeting of this disease. The synovial sarcoma X chromosome breakpoint (SSX) proteins comprise a set of cancer-testis antigens that are upregulated in MHC class I-deficient germline cells and in various types of advanced cancers with a poor prognosis. Humoral and cell-mediated immune responses to the SSX family member SSX2 can arise spontaneously in prostate cancer patients. Thus, SSX2 and other proteins of the SSX family may offer useful targets for tumor immunotherapy. In this study, we evaluated the expression of SSX family members in prostate cancer cell lines and tumor biopsies to identify which members might be most appropriate for immune targeting. We found that SSX2 was expressed most frequently in prostate cell lines, but that SSX1 and SSX5 were also expressed after treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine. Immunohistochemical analysis of microarrayed tissue biopsies confirmed a differential level of SSX protein expression in human prostate cancers. Notably, SSX expression in patient tumor samples was restricted to metastatic lesions (5/22; 23%) and no expression was detected in primary prostate tumors examined (0/73; P < 0.001). We determined that cross-reactive immune responses to a dominant HLA-A2-specific SSX epitope (p103-111) could be elicited by immunization of A2/DR1 transgenic mice with SSX vaccines. Our findings suggest that multiple SSX family members are expressed in metastatic prostate cancers which are amenable to simultaneous targeting.
BACKGROUND: In multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of cancer testis antigens which can be classified by varying expression in normal tissue: restricted to testis, expressed in testis and brain and not restricted but selectively expressed in testis.
DESIGN AND METHODS: Evaluation of cancer testis antigen expression was made in newly diagnosed multiple myeloma cases (HOVON-65/GMMG-HD4 trial; n = 320) and in relapse cases (APEX, SUMMIT, CREST trials; n = 264). Presence of expression using Affymetrix GeneChips was determined for 123 cancer testis antigens. Of these 87 had a frequency of more than 5% in the newly diagnosed and relapsed patients, and were evaluated in detail.
RESULTS: Tissue restriction was known for 58 out of 87 cancer testis antigens. A significantly lower frequency of presence calls in the relapsed compared to newly diagnosed cases was found for 3 out of 13 testis restricted genes, 2 out of 7 testis/brain restricted genes, and 17 out of 38 testis selective genes. MAGEC1, MAGEB2 and SSX1 were the most frequent testis-restricted cancer testis antigens in both data sets. Multivariate analysis demonstrated that presence of MAGEA6 and CDCA1 were clearly associated with shorter progression free survival, and presence of MAGEA9 with shorter overall survival in the set of newly diagnosed cases. In the set of relapse cases, presence of CTAG2 was associated with shorter progression free survival and presence of SSX1 with shorter overall survival.
CONCLUSIONS: Relapsed multiple myeloma reveals extensive cancer testis antigen expression. Cancer testis antigens are confirmed as useful prognostic markers in newly diagnosed multiple myeloma patients and in relapsed multiple myeloma patients. The HOVON-65/GMMG-HD4 trial is registered under Dutch trial register n. NTR-213. CREST, SUMMIT and APEX trials were registered under ns. M34100-024, M34100-025 and NCT00049478/NCT00048230, respectively.
Geiersbach K, Rector LS, Sederberg M, et al.Unknown partner for USP6 and unusual SS18 rearrangement detected by fluorescence in situ hybridization in a solid aneurysmal bone cyst.
Cancer Genet. 2011; 204(4):195-202 [PubMed
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USP6 rearrangement is the most common genetic abnormality in primary aneurysmal bone cyst, and SS18 rearrangement has not been previously described in any type of tumor where synovial sarcoma was excluded from the differential diagnosis. We report a case of solid aneurysmal bone cyst in which fluorescence in situ hybridization (FISH) analysis indicated rearrangements of both USP6 and SS18, but histologic features were consistent with aneurysmal bone cyst throughout the lesion. Reverse-transcription polymerase chain reaction (RT-PCR) for the SS18-SSX1 and SS18-SSX2 translocations, identity testing, and SS18 FISH were performed on cytogenetic monolayer cultures and formalin-fixed paraffin-embedded (FFPE) tissue. Genomic microarray, FISH, and immunohistochemistry were performed on follow-up studies of the FFPE specimen. The karyotype was 45,X,add(X)(p11.2),add(4)(q13),add(8)(p21),-13,add(17)(p11.2),add(18)(q11.2) in all 20 cells analyzed from monolayer cultures. The karyotype showed no cytogenetically visible alterations of chromosomal regions harboring known partners for USP6. Metaphase FISH with a commercial SS18 break-apart probe showed translocation of the 5' portion of the SS18 probe to the short arm of the derivative X, as is observed in synovial sarcoma. RT-PCR showed no evidence of a SS18-SSX fusion, and immunohistochemistry was negative for TLE1, EMA, and cytokeratin AE1/3 expression. FISH on FFPE sections with a custom break-apart probe flanking USP6 showed evidence for a USP6 rearrangement throughout the tumor (25-50%). FISH on FFPE sections with a commercial SS18 break-apart FISH probe showed more variable results (0-50% split signals). There was no evidence of a SS18-USP6 fusion by FISH or RT-PCR. A molecular inversion probe array revealed a deletion encompassing the entire SS18 gene and its promoter, as well as portions of the region targeted by the commercial SS18 FISH probe. In conclusion, results obtained from commercially available FISH probes may occasionally yield misleading results. In this case, the SS18 rearrangement by FISH resulted from a complex rearrangement of 18q11.2 with a deletion of the SS18 gene. The translocation partner for USP6 remains unknown in this case.
Chromosomal translocations are a major source of genetic abnormalities causally linked to certain malignancies. Synovial sarcoma is an aggressive soft tissue tumor characterized by a chromosomal translocation between chromosome 18 and X, generating oncoproteins such as SYT-SSX1 and SYT-SSX2. The molecular mechanism underlying the oncogenic potential of SYT-SSX1/2 is not clear. Here we show that SYT-SSX1 leads to up-regulation of NCOA3, a protein critical for the formation of various cancers. The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. NEMO has also been shown to physically interact with NCOA3. Increased sumoylation of NCOA3 leads to its increased steady state level and nuclear localization. Our findings represent the first example that an oncoprotein directly regulates substrate modification by a SUMO E3 ligase, and leads to overexpression of a protein essential for tumor formation. Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma.
Devarakonda VS, Lembert L, Entwistle JW, Hoag JBPrimary synovial sarcoma of the lung with intra-cardiac extension.
Respiration. 2011; 81(3):249-52 [PubMed
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Synovial sarcomas are a distinct clinical entity occurring most often in the lower extremities. They account for 10-14% of all soft tissue sarcomas. Pulmonary synovial sarcomas are quite rare and account for less than 0.5% of all intra-thoracic neoplasms. We present the first reported case of primary pulmonary synovial sarcoma with intra cardiac extension in a 53-year-old male who presented with chronic cough. Imaging revealed a large right upper lobe mass extending through the superior pulmonary veins into the left atrium. The patient underwent a right total pneumonectomy with extraction of the left atrial mass and left atrial reconstruction. Pathology and immunohistochemistry was diagnostic of primary pulmonary synovial sarcoma positive for SYT-SSX1 gene fusion transcription.
Synovial sarcoma (SS), 3-5% of which occurs in the head and neck region, has generally been regarded as high grade sarcoma. Recent analysis of clinical, morphological, and molecular characteristics of SS, however, identified low and high risk group of patients, resulting in important implications for the treatment of patients diagnosed with SS. We describe the case of a 31-year-old male who presented with biphasic SS with poorly differentiated areas (clinical stage IIA) in a palatine tonsil, an extremely rare site of SS. Molecular analyses revealed typical t(X;18) translocation of the SYT gene and a SYT/SSX1 fusion type. The tumor was surgically resected with free margins. Adjuvant radiotherapy or chemotherapy was not considered indicated. To date, the patient has remained free of tumor for 4 years after surgery. Literature review reveals that primary tonsillar HNSS has previously been documented only in three patients. In all of these patients the tumor was histologically biphasic; however only one published case and the case presented here showed areas of poor differentiation. We discuss the relevance of the presented findings with regard to prognostic and therapeutic considerations in SS in the head and neck region.
Motoi T, Kumagai A, Tsuji K, et al.Diagnostic utility of dual-color break-apart chromogenic in situ hybridization for the detection of rearranged SS18 in formalin-fixed, paraffin-embedded synovial sarcoma.
Hum Pathol. 2010; 41(10):1397-404 [PubMed
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Pathological diagnosis of synovial sarcoma is often problematic due to its broad spectrum of histology. Because synovial sarcoma consistently carries a specific chromosomal translocation, t(X;18), and its derivative chimeric gene, either SS18-SSX1 or SS18-SSX2, detecting these abnormalities by reverse transcription polymerase chain reaction or fluorescence in situ hybridization has been recognized as a powerful aid for diagnosis. Recently, chromogenic in situ hybridization, which enables simultaneous visualization of both genomic abnormality and the morphology of tumor cells, has gained attention. This study investigated the diagnostic utility of dual-color break-apart chromogenic in situ hybridization as a novel method for detecting SS18 rearrangement in synovial sarcoma. Formalin-fixed, paraffin-embedded tissue samples from 16 cases of synovial sarcoma and 10 cases of 5 other types of soft tissue sarcoma were collected. Dual-color break-apart probes were designed against the genomic region adjacent to SS18. Fluorescence and chromogenic in situ hybridization studies were performed using the same sections. In both assays, the number of signals was counted for sixty nuclei per sample. Scoring ratios (unpaired signals/paired signals) were calculated. Subsequently, SS18-SSX1 and SS18-SSX2 were examined by reverse transcription polymerase chain reaction. The results of chromogenic in situ hybridization, fluorescence in situ hybridization, and reverse transcription polymerase chain reaction were correlated. Unpaired signals were clearly observed in all the synovial sarcoma samples, which mostly indicated rearranged SS18. Synovial sarcoma and non-synovial sarcoma samples were clearly distinguished from each other by the scoring ratios. Reverse transcription polymerase chain reaction demonstrated SS18 chimeric gene transcripts in all the synovial sarcoma cases, while no fusion genes were detected in the non-synovial sarcoma cases. Taken together, unpaired signals in synovial sarcoma reflected rearranged SS18. The present chromogenic in situ hybridization-based SS18 rearrangement detection system provides a highly sensitive and specific method for the diagnosis of synovial sarcoma. Chromogenic in situ hybridization-based methods have great potential for routine use in the diagnosis of synovial sarcoma.
Takenaka S, Naka N, Araki N, et al.Downregulation of SS18-SSX1 expression in synovial sarcoma by small interfering RNA enhances the focal adhesion pathway and inhibits anchorage-independent growth in vitro and tumor growth in vivo.
Int J Oncol. 2010; 36(4):823-31 [PubMed
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Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by a unique t(X;18) translocation resulting in expression of SS18-SSX fusion protein. In order to investigate the biological function of this fusion protein and to develop a novel therapeutic option, we examined downregulation of SS18-SSX1 expression by small interfering RNA targeting SS18-SSX1 in three human SS cell lines. Microarray analysis comparing SS18-SSX1-silenced cells with control cells in three SS cell lines showed that SS18-SSX1 mainly affected the focal adhesion pathway. In accord with the array data, silencing of SS18-SSX1 enhances adhesion to the extracellular matrix through the induction of expression of myosin light-chain kinase. Furthermore, the silencing of SS18-SSX1 inhibits anchorage-independent growth in vitro and systemic delivery of siRNA against SS18-SSX1 using a nanoparticle system inhibited tumor growth in a nude mouse xenograft model. Our results demonstrate that siRNA targeting of SS18-SSX1 has therapeutic potential for the treatment of SS.
Kawano D, Yoshino I, Shoji F, et al.Synovial sarcoma of the chest wall.
Gen Thorac Cardiovasc Surg. 2010; 58(2):95-7 [PubMed
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We here report a rare case of synovial sarcoma of the chest wall. A 71-year-old Japanese woman noticed a left anterior chest wall mass after twice having had surgery for lung cancer. An aspiration biopsy diagnosed synovial sarcoma. She then underwent a surgical resection. Pathology examination revealed a biphasic-type synovial sarcoma. When the prepared RNA from the tumor was subjected to a polymerase chain reaction, SYT-SSX1 fusion gene transcripts were demonstrated. Patients with the SYT-SSX1 fusion gene have a worse clinical outcome than patients with SYT-SSX2-positive tumors. After a second surgery, performed in 1 year later, there was no evidence of recurrence for 30 months; however, careful observation may be required.
Wang ZH, Wang XC, Xue MClinicopathologic analysis of 4 cases of primary renal synovial sarcoma.
Chin J Cancer. 2010; 29(2):212-6 [PubMed
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BACKGROUND AND OBJECTIVE: Primary renal synovial sarcoma is rare and might be misdiagnosed as another renal tumor. This study demonstrates the clinicopathologic and immunohistochemical features, differential diagnosis, and prognosis of such tumors.
METHODS: Histologic slides and clinical data were reviewed for 4 patients with primary renal synovial sarcoma and immunohistochemical staining was performed. Molecular analysis was performed on 2 cases to demonstrate the presence of the SYT-SSX gene fusion transcripts by reverse transcriptase polymerase chain reaction (RT-PCR).
RESULTS: The patients were 2 women and 2 men aged from 32 to 48 years. The tumors were 10.0-15.0 cm in diameter, grey-white and solid, and hemorrhage or necrosis was observed. Microscopically, the tumors consisted of mitotically active, monomorphic plump spindle cells with indistinct cell borders growing in short, intersecting fascicles. Hypocellular myxoid areas and a prominent hemangiopericytomatous pattern were present in all cases. The average mitotic rate was 5-8 mitoses/10 high-power fields. Hemorrhage and tumor necrosis were easily found. Scattered small cysts lined with flat, cuboidal, or hobnailed epithelia were found in 3 cases. Tumor cells are immunoreactive for Vimentin (4/4), Bcl-2 (4/4), CD99 (4/4), and CD56 (3/4), and focally for EMA (3/4) and Cytokeratin (3/4). SYT-SSX1 gene fusion was detected in the 2 cases in which RT-PCR analysis was performed. One patient had tumor metastasis to the lung 6 months after surgery and died 5 months later. Multiple metastasis to the liver occurred in one patient and the patient died 13 months after the initial surgery. The other 2 patients had tumors recur at 8 and 15 months and died at 18 and 21 months, respectively, after the initial operation.
CONCLUSION: Primary renal synovial sarcoma is rare, with poor prognosis, characterized by SYT-SSX gene fusion, and needs to be differentiated from other renal sarcomas.
The type I melanoma antigen gene (MAGE) proteins CT7 (MAGE-C1) and MAGE-A3 are commonly expressed in multiple myeloma (MM), and their expression correlates with increased plasma cell proliferation and poor clinical outcome. They belong to the cancer-testis antigen (CTAg) group of tumor-associated proteins, some of which elicit spontaneous immune responses in cancer patients. CT7 and MAGE-A3 are promising antigenic targets for therapeutic tumor vaccines in myeloma; therefore, it is critical to determine if they are immunogenic in MM patients. We analyzed cellular and humoral immune responses against CTAgs in patients with plasma cell dyscrasias: MM, monoclonal gammopathy of undetermined significance (MGUS), and Waldenström's macroglobulinemia (WM). Bone marrow lymphocytes from two of four untreated MM patients exhibited CT7-specific cellular immune responses as measured by an autologous cellular immunity assay, the first such immune response to CT7 to be reported in cancer patients. Sera from 24 patients were screened by ELISA for humoral immune responses to CTAgs. Two patients with MM demonstrated positive titers, one for MAGE-A1 and the other for SSX1. These data demonstrate that CTAgs, particularly CT7, are immunogenic in MM patients and merit further exploration as targets of immunological therapy in MM.