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.
t(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.
t(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).
Accurate diagnoses of sarcoma are sometimes challenging on conventional histomorphology and immunophenotype. Many specific genetic aberrations including chromosomal translocations have been identified in various sarcomas, which can be detected by fluorescence in situ hybridization and polymerase chain reaction analysis. Next-generation sequencing-based RNA sequencing can screen multiple sarcoma-specific chromosome translocations/fusion genes in 1 test, which is especially useful for sarcoma without obvious differentiation. In this report, we utilized RNA sequencing on formalin-fixed paraffin-embedded (FFPE) specimens to investigate the possibility of diagnosing sarcomas by identifying disease-specific fusion genes. Targeted RNA sequencing was performed on 6 sarcoma cases. The expected genetic alterations (clear cell sarcoma/EWSR1-ATF1, Ewing sarcoma/EWSR1-FLI1, myxoid liposarcoma/DDIT3-FUS) in four cases were detected and confirmed by secondary tests. Interestingly, three SS18 fusion genes (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) were identified in a synovial sarcoma case. A rare fusion gene (EWSR1-PATZ1) was identified in a morphologically challenging case; which enabled us to establish the diagnosis of low grade glioneural tumor. In conclusion, RNA sequencing on FFPE specimen is a reliable method in establishing the diagnosis of sarcoma in daily practice.
Nicola M, Onorati M, Bertola G, et al. Primary thyroid biphasic synovial sarcoma and synchronous papillary carcinoma: report of a remarkable case. Pathologica. 2018; 110(2):106-110 [PubMed] Related Publications
Synovial Sarcoma (SS) is the fourth most common soft tissue sarcoma, characterized by translocation t(X;18) (p11.2;q11.2). Although its histological features have been extensively described, this entity is characterized by a wide morphological spectrum so that the recognition can be very challenging at atypical anatomical localization, like the thyroid. We describe a case of a 42-ys-old female patient complaining a cervical swelling due to left intrathyroid nodule, measuring 35 mm in its greatest dimension. A Fine Needle Aspiration Cytology (FNAC) was performed and diagnosis of indeterminate neoplastic lesion, indefinite whether primary or metastatic, was formulated. After complete thyroidectomy, the histological picture of the nodule was characterized by a dual cellular population: several glandular structures composed by columnar cells with clear cytoplasm were embedded in a highly cellular stroma composed of spindle-shaped elements. Immunohistochemistry and molecular biology confirmed the morphological suspicion of SS identifying the fusion transcript SYT-SSX1 and thus ruling out several differential diagnoses which include more common thyroid malignancies. Moreover a synchronous papillary microcarcinoma was detected in the controlateral lobe. This case is noteworthy since it describes the synchronous presence in the thyroid of two completely different malignancies, the first one belonging to the soft tissue neoplasm category and the other one originating from the thyroid follicular epithelium.
Riggi N, Cironi L, Stamenkovic I Synovial sarcoma: when epigenetic changes dictate tumour development. Swiss Med Wkly. 2018; 148:w14667 [PubMed] Related Publications
Synovial sarcoma is a highly aggressive soft tissue malignancy that often affects adolescents and young adults. It is associated with a unique chromosomal translocation that results in the formation and expression of the fusion gene SS18-SSX, which underlies its pathogenesis. Although SS18-SSX provides a potentially unique therapeutic target, all attempts to neutralise it have been unsuccessful thus far. When complete surgical removal of the tumour fails, therapy is limited to largely ineffective cytotoxic drug regimens. Nevertheless, recent discoveries about the mechanisms of SS18-SSX protein function have provided insight into potential alternative therapeutic strategies. SS18-SSX displays oncogenic activity through protein-protein interactions and participation in chromatin remodelling complexes. This review summarises our current understanding of the function of SS18-SSX and the mechanisms by which it alters the epigenetic landscape of permissive cells to induce transformation and the subsequent development of synovial sarcoma.
Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.
Tang S, Dodd LG CIC-DUX4 sarcoma diagnosed by fine-needle aspiration cytology: A case report. Diagn Cytopathol. 2018; 46(11):958-963 [PubMed] Related Publications
The CIC-DUX4 sarcoma is a small round blue cell sarcoma which presents like extraskeletal Ewing sarcoma, but is negative for the EWSR1 gene translocation. The recognition of CIC-DUX4 sarcomas as an aggressive sarcoma may be challenging in fine needle aspirates or small needle core biopsies. We present a case of a 13-year-old female with a fine needle aspiration (FNA) and core needle biopsy (CNB) of a thigh mass showing CIC-DUX4 sarcoma. Cytologic findings include tumor cells with high nuclear to cytoplasmic (N:C) ratio, eccentric nuclei and small nucleoli. The tumor cells were arranged in sheets and singly dispersed with background necrosis. Mitotic figures and apoptosis were present. These findings are similar to cases previously reported. Other reported findings of spindled nuclei, clear cell change and lobular growth pattern were not seen in our case. Immunohistochemical stains showed tumor cells positive for CD99, WT1, vimentin and negative for pancytokeratin, desmin and myogenin, which is the pattern similar to cases previously reported. However, our case was also positive for BCL-2. Fluorescence in situ hybridization (FISH) was negative for EWSR1 and SS18 (SYT) rearrangements and positive for CIC gene rearrangement. On balance, if the following features are seen: (1) a small round blue cell tumor with histomorphology more atypical than that of Ewing sarcoma, (2) cytoplasmic CD99 staining, nuclear WT1 positivity, negative keratin, desmin and myogenin; and (3) EWSR1 rearrangement negative by FISH, then molecular testing for CIC-DUX4 sarcoma should be considered.
Mihály D, Nagy N, Papp G, et al. Release of circulating tumor cells and cell-free nucleic acids is an infrequent event in synovial sarcoma: liquid biopsy analysis of 15 patients diagnosed with synovial sarcoma. Diagn Pathol. 2018; 13(1):81 [PubMed] Free Access to Full ArticleRelated Publications
BACKGROUND: Synovial sarcoma is a rare soft tissue tumor which contains the unique SS18-SSX1, SS18-SSX2 - or, rarely, SS18-SSX4 - fusion transcripts. It is well known that some soft tissue tumors, like Ewing sarcomas and myxoid liposarcomas, can spread via the blood with free circulating tumor cells (CTC); this can be detected by several sensitive molecular biology methods. Here we report a study of fifteen synovial sarcoma patients with varied clinical backgrounds. METHOD: After blood withdrawal and nucleic acid isolation, we attempted to detect the SS18-SSX fusion genes from circulating tumor cells or cell-free nucleic acids with nested PCR and droplet digital PCR. RESULTS: SS18-SSX2 fusion transcript was identified in a small copy number with droplet digital PCR in one case. Nested PCR could not detect any of the fusion transcripts in the examined 15 synovial sarcoma cases. CONCLUSIONS: Heretofore two case reports could detect CTCs in synovial sarcoma - in the first paper, the patient was diagnosed with poorly differentiated type while the other had a rare primary gastric synovial sarcoma. However, until now, no other studies have detected CTCs in the peripheral blood of synovial sarcoma patients. Based on our findings, we can conclude that detection of the chimeric SS18-SSX fusion gene after surgical excision and/or chemotherapy/radiotherapy is a rare circumstance and hence in itself is not sufficient for monitoring the tumor recurrence. Therefore, monitoring of other possible biomarkers - for example synovial sarcoma specific miRNAs - is recommended.
Natarajan V, Ramanathan P, Gopisetty G, et al. In silico and in vitro screening of small molecule Inhibitors against SYT-SSX1 fusion protein in synovial sarcoma. Comput Biol Chem. 2018; 77:36-43 [PubMed] Related Publications
Synovial sarcoma (SS) is characterized by a tumour specific chromosomal translocation t(X;18) (p11;q11) which results in the formation of SYT-SSX1 fusion protein. This fusion protein represents a clear therapeutic target and molecules specifically targeting SYT-SSX1 fusion protein are currently not available. In this study, SYT-SSX1 fusion protein sequence was retrieved from Uniprot and 3D structure was generated using I-TASSER modeling program. A structure based computational screening approach has been employed using Glide docking software to identify potential SYT-SSX1 small molecule inhibitors that bind to the junction region of the fusion protein. The obtained inhibitors were further filtered based on the docking score and ADME/T properties. Ten best fit compounds were chosen for in vitro studies. The anti-proliferative activities of these 10 compounds were screened in Yamato, ASKA (carries SYT-SSX1 fusion protein) and other sarcoma cell lines such as A673, 143B to understand the specificity of inhibition of the chosen compounds. The in vitro activity was compared against HEK293 cell lines. The compound 5-fluoro-3-(1-phenyl-1H-tetraazol-5-yl)-1H-indole (FPTI) was found to be selectively cytotoxic in synovial sarcoma cell lines (Yamato and ASKA) and this compound also showed insignificant anti proliferative activity on other cell lines. Further, target gene expression study confirmed that FPTI treatment down-regulated SYT-SSX1 and modulated its downstream target genes. Cell cycle analysis revealed the involvement of an apoptotic mechanism of cell death. Further experimental validations may elucidate the therapeutic potentials of FPTI against SYT-SSX1 fusion protein.
MiR-206 is a remarkable miRNA because it functions as a suppressor miRNA in rhabdomyosarcoma while at the same time, as previously showed, it can act as an oncomiRNA in SMARCB1 immunonegative soft tissue sarcomas. The aim of this study was to investigate the effect of miR-206 on its several target genes in various human tumorous and normal cell lines. In the current work, we created miR-206-overexpressing cell lines (HT-1080, Caco2, iASC, and SS-iASC) using permanent transfection. mRNA expression of the target genes of miR-206 (SMARCB1, ACTL6A, CCND1, POLA1, NOTCH3, MET, and G6PD) and SMARCB1 protein expression were examined with quantitative real-time polymerase chain reaction, immunoblotting, immunocytochemistry, and flow cytometry. MiRNA inhibition was used to validate our results. We found a diverse silencing effect of miR-206 on its target genes. While an overall tendency of downregulation was noted, expression profiles of individual cell lines showed large variability. Only CCND1 and MET were consistently downregulated. MiR-206 had an antiproliferative effect on a normal human fibroblast cell line. A strong silencing effect of SMARCB1 in miR-206 transfected SS-iASC was most likely caused by the synergic influence of the SS18-SSX1 fusion protein and miR-206. In the same cell line, a moderate decrease of SMARCB1 protein expression could be observed with immunocytochemistry and flow cytometry. In the most comprehensive analysis of miR-206 effects so far, a modest but significant downregulation of miR-206 targets on the mRNA level was confirmed across all cell lines. However, the variability of the effect shows that the action of this miRNA is largely cell context-dependent. Our results also support the conception that the oncomiR effect of miR-206 on SMARCB1 plays an important but not exclusive role in SMARCB1 immunonegative soft tissue sarcomas so it can be considered important in planning the targeted therapy of these tumors in the future. Impact statement Mir-206 is a very unique microRNA because it can act as a suppressor miRNA or as an oncomiRNA depending on the tumor tissue. In SMARCB1 negative soft tissue sarcomas miR-206 is overexpressed, so thus in epithelioid and synovial sarcomas it functions as an oncomiRNA. MiR-206 has diverse silencing effects on its target genes. We found that the action of miR-206 is largely cell context dependent. The oncomiR role of miR-206 is crucial but not exclusive in SMARCB1 negative soft tissue sarcomas and miR-206 has an antiproliferative effect on a normal human fibroblast cell line. Expressions of miR-206 targets observed in tumors can only be reproduced in the corresponding tumorous cell lines. This is the first study which examined the permanent effect of miR-206 on its target genes in normal, tumor, and genetically engineered cell lines.
Morgan MA, Shilatifard A Epigenetic ConFUSION: SS18-SSX Fusion Rewires BAF Complex to Activate Bivalent Genes in Synovial Sarcoma. Cancer Cell. 2018; 33(6):951-953 [PubMed] Related Publications
In this issue of Cancer Cell, McBride and colleagues report that the synovial sarcoma SS18-SSX fusion drives BAF complex recruitment to bivalent domains repressed by PRC2 complex to orchestrate aberrant transcriptional activation. Redistribution of BAF localization is a major driver of synovial sarcoma proliferation and presents a promising therapeutic target.
Panigrahi MK, Pradhan G, Sahoo N, et al. Primary pulmonary synovial sarcoma: A reappraisal. J Cancer Res Ther. 2018 Apr-Jun; 14(3):481-489 [PubMed] Related Publications
Synovial sarcoma (SS) is a malignant mesenchymal tumor with variable epithelial differentiation that affects mostly young adults and can arise at any anatomic site. Primary intrathoracic SS is very rare accounting for <0.5% of all lung tumors. Most commonly, it arises from the lung followed by pleura and mediastinum. Primary pulmonary SS (PPSS) affects both sexes equally with no preference for any hemithorax. The morphology, immunostaining properties, cytogenetic features, and management strategy of PPSS are similar to that of soft tissue SS. Histologically, there are two main types of SS - monophasic and biphasic with a feature of poor differentiation seen in both types. Most patients present with large intrathoracic masses with or without ipsilateral pleural effusion. Bone invasion or mediastinal adenopathy is very rare. SS is characterized by a specific chromosomal translocation producing SS18-SSX fusion gene in more than 90% of cases. Identification of this fusion gene remains the gold standard for the diagnosis in the presence of consistent histology and immunophenotype. Multimodality treatment including wide excision, chemotherapy, and radiotherapy is the mainstay of therapy. SS is relatively chemosensitive, and ifosfamide-based regimen showed improved survival in metastatic disease. Generally, SS is considered as high-grade tumors with a poor prognosis. Novel therapies targeted at fusion oncogene, SS18-SSX-derived peptide vaccine, epidermal growth factor receptor, and vascular endothelial growth factor are the future hope in SS. We describe a prototype case and present an elaborate review on primary SS of lung.
McBride MJ, Pulice JL, Beird HC, et al. The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. Cancer Cell. 2018; 33(6):1128-1141.e7 [PubMed] Related Publications
Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.
Vargas AC, Selinger C, Satgunaseelan L, et al. FISH analysis of selected soft tissue tumors: Diagnostic experience in a tertiary center. Asia Pac J Clin Oncol. 2019; 15(1):38-47 [PubMed] Related Publications
AIM: Fluorescence in situ hybridization (FISH) is an important ancillary tool for the classification of bone/soft tissue (BST) tumors. The aim of this study was to evaluate the contribution of FISH to the final classification of common BST entities in the molecular pathology department of the Royal Prince Alfred Hospital (RPAH), which is one of the most important referral centers for the management of sarcomas in Australia. METHODS: All routine diagnostic FISH tests performed on BST formalin-fixed paraffin embedded (FFPE) tissue specimens at the RPAH in a 5-year period (February, 2010-November, 2015) were reviewed. FISH analyses presented in this study include commercial break-apart probes (SS18, FUS, DDIT3, FUS, USP6, PDGFB, TFE3 and ALK) and a single enumeration (MDM2) probe. RESULTS: There were 434 interpretable FISH assays on BST samples including MDM2 (n=180), SS18 (n=97), FUS (n=64), DDIT3 (n=37), USP6 (n=30), PDGFB (n=13), TFE3 (n=8) and ALK (n=5). Discrepancies between the histopathological diagnosis and the FISH results were seen in 12% of the cases. In this subset of discordant cases, FISH contributed to the re-classification of 7% of cases originally diagnosed as synovial sarcoma (SS18) and 6% of adipocytic neoplasms (MDM2) based on the presence or absence of the expected gene alteration. CONCLUSION: Our study confirms that paraffin FISH is a sensitive and specific ancillary tool in the diagnosis of BST neoplasms when used in the appropriate clinicopathological context. These findings highlight the need for further ancillary molecular tools in the diagnosis and characterization of challenging cases.
Zayed H, Petersen I Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors. Pathol Res Pract. 2018; 214(7):1000-1007 [PubMed] Related Publications
BACKGROUND: SOX2 has gained considerable interest as a pluripotency inducing gene. Co-transfection of SOX2 together with NANOG, KLF4 and c-MYC into adult fibroblasts was able to generate pluripotent stem cells. SOX2 has been reported to be expressed in synovial sarcoma, a tumor being characterized by the SS18-SSX gene fusion forming part of the SWI/SNF chromatin remodeling complex that affects histone methylation. The role of SOX2 in this tumor type as well as other soft tissue tumor entities however is still poorly characterized. We analyzed SOX2 protein expression in soft tissue tumors. Alongside we tested Histone H3 expression (H3K27me3) in SOX2 positive cases to investigate this epigenetic mark and its correlation with the SOX2 status and clinicopathological parameters. METHODOLOGY: In total, 60 samples of synovial sarcomas from the reference center for soft tissue tumors at the institute of pathology of the Jena University hospital were included into the study along with 343 other tissue tumors. Protein analysis was done by immunohistochemistry of tissue microarrays. All synovial sarcoma cases were confirmed by molecular testing using SS18 FISH break apart probes. RESULTS: SOX2 reactivity was detectable in 35 synovial sarcoma cases (58.3%) while 25 (41.7%) were negative. Only 13 cases of the other 343 soft tissue tumors, varying from nodular fasciitis to undifferentiated pleomorphic sarcoma, revealed a SOX2 expression, 12 out of these were undifferentiated high grade sarcoma. There was no obvious correlation with the clinicopathological data. H3K27me3 immunohistochemistry of the synovial sarcoma cases revealed a high statistically significant correlation between SOX2 and H3K27me3 expression (p < 0,0005, Chi square test). Similar to SOX2, there was no correlation between H3K27me3 expression and tumor grade. Six SOX2 positive synovial sarcoma cases were analyzed by FISH using a SOX2/CEN3 dual color FISH probe. None of these cases revealed an amplification of the SOX2 gene. CONCLUSION: The data confirms previous studies reporting SOX2 and H3K27me3 expression in synovial sarcoma and reveals that both biomarkers are related to each other. It strengthens the notion that the tumor type is driven by epigenetic processes similar to those that are operating in pluripotent stem cells. The relevance of these parameters in the pathway pathology of synovial sarcoma, i.e. the timing and dosing of SOX2 and H3K27me3 expression initiated by the SS18-SSX driver mutation together with the interplay of these events with other signaling pathways, cellular mechanisms and additional mutations in tumor progression, will require further studies.
Alegría-Landa V, Nájera L, Massa DS, et al. Primary Subcutaneous Synovial Sarcoma: First Reported Subcutaneous Case Showing TLE1 Immunoreactivity. Am J Dermatopathol. 2018; 40(10):772-777 [PubMed] Related Publications
Synovial sarcoma (SS) accounts for 5%-10% of all soft tissue sarcomas. It is a well-defined soft tissue neoplasm with biphasic and monophasic histologic subtypes and unknown histogenesis. It usually occurs in the extremities, especially the thigh-knee region of young adults. Recurrences are frequent and distant metastasis developed in approximately half of the patients. SSs are characterized by a recurrent nonrandom chromosomal translocation, t(X; 18) (p11; q11), which is considered the primary genetic event in more than 90% of cases. Only 4 cases of cutaneous and subcutaneous SSs have been published in the literature so far. We report a case of primary subcutaneous SS in the forearm of a young woman and discuss the histopathologic differential diagnosis with other similar neoplasms. This is the first reported case of primary cutaneous SS showing immunoreactivity for TLE1 in the nuclei of neoplastic cells, supporting the use of this marker for diagnosis of this rare cutaneous neoplasm.
Oyama R, Kito F, Sakumoto M, et al. Establishment and proteomic characterization of a novel synovial sarcoma cell line, NCC-SS2-C1. In Vitro Cell Dev Biol Anim. 2018; 54(5):392-399 [PubMed] Related Publications
Synovial sarcoma is an aggressive mesenchymal tumor, characterized by the presence of unique transfusion gene, SS18-SSX. Cell lines enable researchers to investigate the molecular backgrounds of disease and the significance of SS18-SSX in relevant cellular contexts. We report the establishment and proteomic characterization of a novel synovial sarcoma cell line. Primary tissue culture was performed using tumor tissue of synovial sarcoma. The established cell line was authenticated by assessing its DNA microsatellite short tandem repeat analysis and characterized by in vitro assay. Proteomic study was achieved by mass spectrometry, and the results were analyzed by treemap. The cell line NCC-SS2-C1 was established from a primary tumor tissue of a synovial sarcoma patient. The cell line has grown well for 11 mo and has been subcultured more than 15 times. The established cells were authenticated by assessing their short tandem repeat pattern comparing with that of original tumor tissue. The cells showed polygonal in shape and formed spheroid when seeded on the low-attachment dish. Proteomic analysis revealed the molecular pathways which are unique to the original tumor tissue or the established cell line. In conclusion, a novel synovial sarcoma cell line NCC-SS2-C1 was successfully established from the primary tumor tissue. The cell line has characteristic transfusion SS18-SSX and poses aggressive in vitro growth and capability of spheroid formation. Thus, NCC-SS2-C1 cell line will be a useful tool for investigation of the mechanisms of disease and the biological role of fusion gene.
Przybyl J, Kidzinski L, Hastie T, et al. Gene expression profiling of low-grade endometrial stromal sarcoma indicates fusion protein-mediated activation of the Wnt signaling pathway. Gynecol Oncol. 2018; 149(2):388-393 [PubMed] Related Publications
OBJECTIVE: Low-grade endometrial stromal sarcomas (LGESS) harbor chromosomal translocations that affect proteins associated with chromatin remodeling Polycomb Repressive Complex 2 (PRC2), including SUZ12, PHF1 and EPC1. Roughly half of LGESS also demonstrate nuclear accumulation of β-catenin, which is a hallmark of Wnt signaling activation. However, the targets affected by the fusion proteins and the role of Wnt signaling in the pathogenesis of these tumors remain largely unknown. METHODS: Here we report the results of a meta-analysis of three independent gene expression profiling studies on LGESS and immunohistochemical evaluation of nuclear expression of β-catenin and Lef1 in 112 uterine sarcoma specimens obtained from 20 LGESS and 89 LMS patients. RESULTS: Our results demonstrate that 143 out of 310 genes overexpressed in LGESS are known to be directly regulated by SUZ12. In addition, our gene expression meta-analysis shows activation of multiple genes implicated in Wnt signaling. We further emphasize the role of the Wnt signaling pathway by demonstrating concordant nuclear expression of β-catenin and Lef1 in 7/16 LGESS. CONCLUSIONS: Based on our findings, we suggest that LGESS-specific fusion proteins disrupt the repressive function of the PRC2 complex similar to the mechanism seen in synovial sarcoma, where the SS18-SSX fusion proteins disrupt the mSWI/SNF (BAF) chromatin remodeling complex. We propose that these fusion proteins in LGESS contribute to overexpression of Wnt ligands with subsequent activation of Wnt signaling pathway and formation of an active β-catenin/Lef1 transcriptional complex. These observations could lead to novel therapeutic approaches that focus on the Wnt pathway in LGESS.
Waterfall JJ, Meltzer PS A Non-canonical Polycomb Dependency in Synovial Sarcoma. Cancer Cell. 2018; 33(3):344-346 [PubMed] Related Publications
Disruptions in the antagonistic balance between the chromatin-modifying Polycomb and Trithorax group proteins drive many malignancies. In this issue of Cancer Cell, Banito et al. describe how the SS18-SSX oncogenic fusion protein in synovial sarcoma directly co-opts these complexes to drive gene dysregulation and sustain the transformed state.
Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.
Kito F, Oyama R, Takai Y, et al. Establishment and characterization of the NCC-SS1-C1 synovial sarcoma cell line. Hum Cell. 2018; 31(2):167-174 [PubMed] Related Publications
Synovial sarcoma is an aggressive mesenchymal malignancy characterized by unique gene fusions. Tissue culture cells are essential tools for further understanding tumorigenesis and anti-cancer drug development; however, only a limited number of well-characterized synovial sarcoma cell lines exist. Thus, the objective of this study was to establish a patient-derived synovial sarcoma cell line. We established a synovial sarcoma cell line from tumor tissue isolated from a 72-year-old female patient. Prepared cells were analyzed for the presence of gene fusions by fluorescence in situ hybridization, RT-PCR, and karyotyping. In addition, the resulting cell line was characterized by viability, short tandem repeat, colony and spheroid formation, and invasion analyses. Differences in gene enrichment between the primary tumor and cell line were examined by mass spectrometric protein expression profiling and KEGG pathway analysis. Our analyses revealed that the primary tumor and NCC-SS1-C1 cell line harbored the SS18-SSX1 fusion gene typical of synovial sarcoma and similar proteomics profiles. In vitro analyses also confirmed that the established cell line harbored invasive, colony-forming, and spheroid-forming potentials. Moreover, drug screening with chemotherapeutic agents and tyrosine kinase inhibitors revealed that doxorubicin, a subset of tyrosine kinase inhibitors, and several molecular targeting drugs markedly decreased NCC-SS1-C1 cell viability. Results from the present study support that the NCC-SS1-C1 cell line will be an effective tool for sarcoma research.
Zhang M, Mao D, Zhang W The pathogenic role of MEF2D-SS18 fusion gene in B-cell acute lymphoblastic leukemia. Biochem Biophys Res Commun. 2018; 496(4):1331-1336 [PubMed] Related Publications
B-cell acute lymphoblastic leukemia (B-ALL) is characterized by various fusion genes resulted from chromosome translocations, and MEF2D related fusions are recently identified in a B-ALL subtype with relatively worse survival. In this study, we investigated the pathogenic role of MEF2D-SS18 fusion in B-ALL. The recombinant retrovirus and lentivirus plasmids containing the MEF2D-SS18 transcript were constructed for functional studies. Immuno-fluorescent staining presented the nuclear localization of MEF2D-SS18. In vitro B cell differentiation assay showed MEF2D-SS18 significantly inhibited the differentiation of mouse common lymphoid progenitors into CD19 positive B cells. The data of RBMT mouse model also showed B cell developmental arrest. In REH cells overexpressing MEF2D-SS18, genes related to B cell development were down-regulated, while genes related to drug sensitivity and B cell survival were up-regulated. In conclusion, MEF2D-SS18 fusion gene blocked the differentiation of B cells, thus exerted a funding role in the pathogenesis and prognosis of B-ALL.
The mammalian SWI/SNF chromatin remodeling complex is a heterogeneous collection of related protein complexes required for gene regulation and genome integrity. It contains a central ATPase (BRM or BRG1) and various combinations of 10-14 accessory subunits (BAFs for
Herrera-Goepfert R Postradiation Synovial Sarcoma of the Common Bile Duct: A Previously Unreported Anatomic Site. Int J Surg Pathol. 2018; 26(5):469-474 [PubMed] Related Publications
Synovial sarcoma is a ubiquitous neoplasm predominantly affecting soft tissues of young adults of any gender; few cases have been described in the digestive system, mostly in the stomach. The (X;18)(p11.2; q11.2) translocation yields unique SS18-SSX fusion genes. Synovial sarcoma has been related to radiotherapy, but no synovial sarcoma has been associated with the digestive system. This article describes the case of a synovial sarcoma arising along the extrahepatic biliary tree, 10 years after the application of an abdominal radiotherapy schedule due to a retroperitoneal metastatic seminoma in a male who developed progressive obstructive jaundice. Ninety percent of the analyzed cells carried the SS18 gene with separation of sequences, thus denoting a translocation. There are only 8 post-radiotherapy synovial sarcomas that have been reported previously, and this is the first report of a radiotherapy-related synovial sarcoma arising from the extrahepatic biliary tree, and the second case described in this anatomic region.
Zhan D, Zhang Y, Xiao P, et al. Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia. Leuk Res. 2018; 65:20-24 [PubMed] Related Publications
Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.
RATIONALE: When a gastric spindle cell tumor is observed, the possibility of synovial carcinoma, besides common mesenchymal tumor, should also be considered. PRESENTING CONCERNS OF THE PATIENT: The patient is a 51-year-old American woman who underwent medical check-up at a general hospital. Upper endoscopy showed a 2-cm sized mass covered with intact mucosa, and a central depression located on the posterior wall of the mid body. Biopsy of the mass showed focal atypical cells proliferation in mucosa on hematoxylin & eosin (H&E) staining. Endoscopic ultrasound showed a 17-mm homogenously hypoechoic mass within the submucosal layer. INTERVENTIONS: After diagnostic endoscopic submucosal dissection was performed, H&E and immunohistochemical staining showed synovial sarcoma (SS). To confirm the diagnosis, reverse transcriptase-polymerase chain reaction was performed, revealing a chimeric transcript of the SYT-SSX1 fusion gene. The diagnosis of primary gastric SS was confirmed because no evidence of possible primary lesions or metastatic lesions was observed. Therefore, the patient underwent distal gastrectomy. OUTCOMES: After surgery, the surgical specimen demonstrated no residual tumor cells. The patient received no adjuvant therapy, and there has been no evidence of local recurrence or distant metastasis for 2 months after the operation. LESSONS: When gastric subepithelial tumor is suspicious, we should also consider gastric SS.
Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in >130 non-SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment.
Dalal S, Nicholson CE, Jhala D Unusual presentation of poorly differentiated primary pulmonary synovial sarcoma (PD-PPSS) diagnosed by EBUS-TBNA with cytogenetic confirmation-A diagnostic challenge. Diagn Cytopathol. 2018; 46(1):72-78 [PubMed] Related Publications
Poorly differentiated primary pulmonary synovial sarcoma (PD-PPSS) is a rare, aggressive neoplasm, which occurs in 0.5% cases of all lung malignancies. The diagnosis of PD-PPSS can be very challenging on cytology samples. We present here an unusual case of PD-PPSS diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), in the setting of known history of diffuse large B-cell lymphoma. Diff-Quik and Papanicolaou stains showed cellular specimen with clusters of highly atypical small round blue cells admixed with lymphoid elements; and some with denuded cytoplasm. Cell block further showed molding, crush artifact and atypical mitotic figures. A differential diagnosis based on extended immunohistochemical work-up was Ewing?s sarcoma/PNET versus poorly differentiated synovial sarcoma. Fluorescent in-situ hybridization (FISH) showed SYT gene rearrangement at 18q11.2. In this report, we describe the cytomorphological features, diagnostic pitfalls, challenges, potential mimics, and importance of acquisition of adequate material for the ancillary work-up on the cell block.
Gupta N, Kenan S, Kahn LB Synovial Sarcoma Mimicking Pleomorphic Hyalinizing Angiectatic Tumor of Soft Parts: A Case Report. Int J Surg Pathol. 2018; 26(1):73-77 [PubMed] Related Publications
Synovial sarcoma is a high-grade sarcoma commonly affecting young adults. The sites of involvement include soft tissue near joints, lung, pleura, mediastinum, larynx, kidney, and buttocks. Histologic types include monophasic, biphasic, and undifferentiated. We report a unique case of synovial sarcoma with low-grade histologic features mimicking pleomorphic hyalinizing angiectatic tumor (PHAT) with indolent behavior for a period of 10 years. The tumor showed angiectatic blood vessels with fibrinous cuffing, hypocellular and hypercellular spindle cell areas with rare mitoses, and focal atypia in a myxoid background. TLE1 was positive with SYT gene translocation detected on fluorescent in situ hybridization. Cases of myxoinflammatory fibroblastic sarcoma and myxofibrosarcoma have been reported as exhibiting histologic features of PHAT. However, to the best of our knowledge, cases of synovial sarcoma mimicking PHAT have not been reported.
Jiang D, Peng R, Yan X, et al. Synovial sarcoma showing loss of a green signal in SS18 fluorescence in situ hybridization: a clinicopathological and molecular study of 12 cases. Virchows Arch. 2017; 471(6):799-807 [PubMed] Related Publications
The phenomenon of losing a green signal in synovial sarcoma (SS) using the SS18 break-apart probe by fluorescence in situ hybridization (FISH) has been poorly described. In this study, 12 SS with missing a green signal were identified. This series included 7 males and 5 females, aged 17 to 69 years (median, 38.5 years). The tumors involved the extremities (50%), mediastinum (16.7%), hypopharynx (8.3%), neck (8.3%), thyroid (8.3%), and retroperitoneum (8.3%). The tumors were classified as monophasic SS (58.3%) and poorly differentiated SS (41.7%). An anaplastic SS showing features of pleomorphic sarcoma was observed. Immunostaining for TLE1, BCL2, CD99, epithelial membrane antigen, cytokeratin (AE1/AE3), cytokeratin 7, S-100 protein, and CD34 was consistent with typical SS. In FISH, all the tumors showed the pattern of 1 to 3 fused signal(s) with 1 to 3 red signal(s), without corresponding a green signal. The fusion transcripts included SS18-SSX1 (8/10, 80%) and SS18-SSX2 (2/10, 20%) fusions. Median and 5-year overall survival were 19.1 months and 43.6%, respectively. In conclusion, we reported a series of SS losing a green signal in the SS18 FISH assay. We propose that this variant FISH pattern should be interpreted as a peculiar unbalanced rearrangement of the SS18 gene and subsequent SS18-SSX fusion test should be recommended. The cases in this study seem to show some unusual clinicopathological features, including unusual locations, higher proportions of poorly differentiated SS, and aggressive clinical course. However, whether this variant FISH pattern is associated with peculiar clinicopathologic features awaits larger series.
Zhou Y, Chen D, Qi Y, et al. Evaluation of expression of cancer stem cell markers and fusion gene in synovial sarcoma: Insights into histogenesis and pathogenesis. Oncol Rep. 2017; 37(6):3351-3360 [PubMed] Related Publications
Synovial sarcoma (SS) is an aggressive soft tissue tumor, with uncertain histological and cellular origin. SYT-SSX is considered to be responsible for sarcoma initiation and progression. The histogenesis and pathogenesis of this tumor are poorly understood, and prognosis of patients of SS is unsatisfactory. Recent studies have shown an association of cancer stem cells with the initiation and development of tumors. We explored immunohistochemical expression level of stem cell associated markers to determine the possible histogenesis and pathogenesis of SS. Fusion gene SYT-SSX was tested to assess diagnostic value and the molecular pathological features. We obtained the clinicopathological data of 20 SS patients, immunohistochemical staining were used to evaluate stem cell-associated markers included CD133, CD29, CD44, nestin, and ALDH1. Fusion gene SYT-SSX was tested by reverse transcriptase-polymerase chain reaction (RT-PCR). Twenty SS cases were observed and the positive immuno-expression results showed CD133 (17/20), CD29 (11/20), CD44 (11/20), nestin (6/20), and ALDH1 (5/20). Fusion gene SYT-SSX was successfully detected by RT-PCR from 18 available samples. The expression of stem cell-associated markers (CD133, CD29, CD44, Nestin, and ALDH1) and clinical data (age, gender, sites, tumor size, histological type, tumor stage, and distant metastases) did not show statistically significant relationship (P>0.05), whereas, statistically significance between ALDH1 and metastases was observed (P<0.01). The ALDH1 positive synovial sarcoma (ALDH1+ SS) cases had significantly poor prognosis compared to ALDH1 negative synovial sarcoma (ALDH1- SS) cases (P<0.05). Immunohistochemical results indicated different expression levels of the five cancer stem cell markers in SS suggesting that SS may arise from cancer stem cells. Fusion gene SYT-SSX may play a critical role in the molecular pathological of SS.
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.