Materiały źródłowe

• #1

  https://www.orthobullets.com/pathology/8052/synovial-sarcoma

  Synovial Sarcoma is a malignant, soft tissue sarcoma caused by a t(X;18) chromosomal translocation mutation (SS18:SSX fusion protein) most commonly found near joints but rarely within the joint. […] Mechanism: mesenchymal soft tissue sarcoma with unknown cellular origin; synovial sarcoma is a misnomer due to the tumor’s microscopic resemblance to mature synovium. […] Chromosomal translocation t(X;18) is observed in more than 90% of cases. […] Translocation forms the SYT-SSX1, 2, or 4 fusion protein. […] Fusion proteins bind to BAF complex, which displaces the tumor suppressor BAF47; new BAF complex activates Sox2, which leads to tumor formation. […] Cellular origin of synovial sarcoma is unknown.

• #1 Synovial Cell Sarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK587366/

  Synovial sarcoma is defined by the translocation between chromosome X and 18, which leads to the expression of SS18:SSX fusion proteins. […] The presence of t(X;18)(p11.2;q11.2) is a pathognomonic feature of synovial sarcoma. […] The pathognomonic translocation between chromosomes X and 18 leads to the expression of several SS18:SSX fusion proteins described in this tumor’s pathogenesis. SS18:SSX1 and SS18:SSX2 (and rarely SS18:SSX4) are the fusion proteins expressed in 95% of patients diagnosed with SS and are essential in establishing the diagnosis. The fusion proteins bind to the BAF complex (BRG1- or HBRM-associated factors), which displaces the tumor suppressor BAF47. The modified BAF complex leads to the activation of Sox2 (sex-determine region Y-box 2), which is necessary for the proliferation of synovial sarcoma.

• #1 Synovial Sarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1257131-overview

  The origin of synovial sarcoma is unclear. Its name notwithstanding, this sarcoma is not associated with synovial joints. The basis for the name synovial cell sarcoma was the similarity between cells of this tumor and primitive synoviocytes. […] A neurologic origin for this sarcoma has been suggested. In fact, there is a histologic resemblance between the neural cells of malignant peripherical nerve sheath tumor (MPNST) and the cells of synovial sarcoma. […] The (X;18)(p11;q11) translocation fuses the SYT gene from chromosome 18 to a homologous gene at Xp11 (SSX1, SSX2, or SSX4). The fusion proteins SYT-SSX1 and SYT-SSX2 are believed to function as aberrant transcriptional regulators, resulting in either activation of proto-oncogenes or inhibition of tumor suppressor genes. […] A correlation appears to exist between the histologic subtype of the tumor and either of these two fusion proteins. Biphasic tumors, containing both epithelial and spindle cell components, express the SYT-SSX1 transcript, whereas monophasic tumors with only a spindle cell component may express either transcript.

• #1 Synovial Sarcoma | Cancer Genetics Web

  http://www.cancerindex.org/geneweb/X200302.htm

  Synovial sarcoma (SS) is a rare tumour, with dismal survival when metastasis occurs. SS contains a characteristic translocation (X;18)(p11;q11) and the fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. […] 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. […] 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. […] Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood.

• #1 Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy

  https://www.mdpi.com/2073-4409/13/20/1695

  Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. […] Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. […] SS pathogenesis is mainly driven by SS18-SSX fusion proteins playing an important role in the regulation of chromatin remodeling. The key epigenetic regulators, switch/sucrose-non-fermentable (SWI/SNF) complexes, are the members of the Trithorax-group protein (TrxG) family. […] The oncogenic SWI/SNF complexes could target PRC-repressed domains and activate them by recruiting RNA Polymerase II and initiating transcription.

• #1 The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1 | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005060

  This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. […] The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. […] This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. […] These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.

• #1 Synovial Sarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/synovial-sarcoma/

  Synovial sarcoma (SS) is a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation. SS is characterized by a specific SS18-SSX1/2/4 fusion gene. […] SS cells are dependent on SS18-SSX expression to maintain their transformed phenotype. Conditional expression of SS18-SSX induces SSs in genetically engineered mouse models, supporting its function as an oncogene when expressed in permissive mesenchymal progenitor cells. Additionally, SS18-SSX1 has been shown to transform primary cell lines. Recent evidence suggests that the SS18-SSX fusion protein disrupts epigenetic control and blocks mesenchymal differentiation by complementary mechanisms including competitive binding with, and displacement of, native SS18 in the SWI/SNF chromatin-remodeling complex, inducing dependency on BRD9-containing alternative SWI/SNF complexes (ncBAF complexes) and colocalizing with factors such as the ATF2 transcription factor, TLE1 to repress ATF2 target genes, and the KDM2B lysine demethylase at unmethylated CpG islands to reactivate repressed genes.

• #1 SSX2 (synovial sarcoma, X breakpoint 2)

  https://atlasgeneticsoncology.org/gene/42406/ssx2-(synovial-sarcoma-x-breakpoint-2)

  SSX2 is gaining importance as a developmental factor involved in the pathogenesis of synovial sarcoma, and as an immunotherapeutic target for several human cancers. […] Synovial sarcoma is characterized by a unique chromosomal translocation event, t(X;18)(p11.2;q11.2) that involves a break in the SS18 gene on chromosome 18 and another in a SSX gene on the X chromosome. When fusion occurs at the breakpoints, it generates a hybrid gene, SS18-SSX, which encodes a potent oncogene. SS18-SSX is thought to initiate tumorigenesis and contribute to the development of synovial sarcoma. […] The molecular function of SS18-SSX is key to cancer development. […] Deregulation of expression programs by SS18-SSX1/2 results in a series of biological events implicated in synovial sarcoma pathogenesis. These events likely include reprogramming of stem cell differentiation, and untimely activation of oncogenic pathways such as IGF2, Wnt, FGF, and ephrin, as well as reactivation of the anti-apoptotic pathway and the bcl-2 oncogene.

• #1

  https://www.omim.org/entry/300813

  The SYT-SSX1 form of synovial sarcoma, compared to the SYT-SSX2 form, has a significantly unfavorable prognosis (Kawai et al., 1998; Ladanyi et al., 2002). This suggests that the SYT-SSX fusion genes may influence molecular mechanisms involved in tumor growth and progression and that SYT-SSX1 has a stronger influence on these mechanisms than SYT-SSX2. […] Xie et al. (2002) used Western blot analysis on 74 fresh, fusion variant-typed tumor samples from localized synovial sarcoma and found a significant correlation between SYT-SSX1 and high expression of cyclin A1 (CCNA1; 604036) and cyclin D1 (CCND1; 168461); P = 0.003 and P = 0.025, respectively. The data suggested that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 variant is due to an accelerated tumor cell proliferation.

• #1 Targeting the Pentose Phosphate Pathway for the Treatment of Synovial Sarcoma – SFA

  https://curesarcoma.org/funded-research/targeting-the-pentose-phosphate-pathway-for-the-treatment-of-synovial-sarcoma/

  Synovial Sarcoma (SS) is a translocation dependent subtype of soft tissue sarcoma that arises from the fusion of SYT and SSX. The hybrid transcript factor SYT:SSX modulates SWI/SNF chromatin remodeling and gene expression. […] We have found that SS cell lines die exceedingly fast within two hours of glucose withdrawal by a mechanism not involving apoptosis or necrosis. In addition, we have identified that glucose-6-phosphate dehydrogenase (G6PD), a glucose metabolizing enzyme at the entrance to the pentose phosphate pathway (PPP), is the key regulatory enzyme needed for the survival of SS after glucose withdrawal. […] When the SYO xenografts are treated in vivo with DHEA, tumor volume decreased dramatically over a time course of seven days and did not recur. […] Finally, we are the first to identify that malic enzyme 1 (ME1) is not expressed in SS cell lines, clinical samples, or tumors from the SS spontaneous transgenic mouse.

• #1 Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma | bioRxiv

  https://www.biorxiv.org/content/10.1101/2022.05.09.490894.full

  Given the high noise due to FFPE samples and the low specificity of the fusion gene identification pipelines, a rigorous filtering process was performed in the FusionCatcher, excluding banned, high common mapping reads, promiscuous genes, low bioinformatics support, adjacent, and short repeats, which were considered to be false positives and were removed before downstream analyses. […] These findings support previous data showing that the primary fusion gene SS18-SSX is the main driver of tumorigenesis in SS. […] We observed that SSC-I was significantly associated with poor survival, metastasis, had significantly highest rates of mitosis and the lowest stromal and immune scores. […] The vascularized-SS (SSC-II) cluster was characterized by better patient outcome. […] The epithelial-SS (SSC-III) was dominated by biphasic tumors and characterized by higher levels of kinase-signaling targets, innate immune cell infiltration and lower levels of proliferation and DNA repair.

• #1 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. […] Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. […] The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. […] Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype.

• #1 Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma | Nature Medicine

  https://www.nature.com/articles/s41591-020-01212-6

  Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. […] Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. […] Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

• #1 Behind the FDA Approval: Afami-Cel in Synovial Sarcoma

  https://www.targetedonc.com/view/behind-the-fda-approval-afami-cel-in-synovial-sarcoma

  Afami-cel is a T-cell receptor. The way it works is that it takes a patient’s own immune cells and redirects them to the type of protein that is found in the patient’s tumor. In this particular case, the protein is called MAGE-A4. […] This form of therapy is an effective therapy for immunologically cold tumors. Synovial sarcoma sort of is a prototype of a type of cancer that has limited immune cells. Other drugs, such as checkpoint inhibitors, have been shown to be relatively ineffective. […] The fact that we can effectively stimulate the immune system with this exogenous administration of a patient’s own immune cell that has been effectively genetically engineered holds promise that this can probably be expanded to other solid tumors that express this protein. […] The standard of care for synovial sarcoma is typically surgery with or without radiation and with or without adjuvant chemotherapy, but unfortunately, 50% of patients develop metastases and, obviously in the setting of metastatic disease, the disease is no longer curable. […] Afami-cel offers a remarkable improvement upon the standard of care, so it is a promising and exciting option for our patients.

• #1 Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy

  https://www.mdpi.com/2073-4409/13/20/1695

  Direct changes in the pathological signaling pathways in SS are associated with SS18-SSX fusion products and their interactors. […] Despite significant advances in the molecular studies of the pathogenesis and progression of SS, surgery combined with neoadjuvant or adjuvant therapies (radiotherapy and chemotherapy) is the standard of care for this cancer type.

• #1 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  SS18::SSX competes with endogenous SS18 to incorporate into the canonical (cBAF) and non-canonical (GBAF) forms of the remodeling complex. […] Incorporation of the fusion protein into cBAF results in its degradation, which in turn increases the relative prevalence of other BAF-family complexes (polybromo-associated (PBAF) and GBAF), altering the BAF subtype balance and genomic distribution. […] The observed synthetic lethality associated with elevated prevalence of GBAF indicated a potential therapeutic vulnerability in SyS, although recent clinical trials focused on targeting BRD9 (a specific component of the GBAF complex) did not show clinical benefit. […] SS18::SSX interacts genetically and physically with numerous epigenetic regulatory proteins including the DNA binding protein ATF2, the transcriptional corepressor TLE1 and members of non-canonical polycomb group repressor complexes.

• #1

  https://www.jci.org/articles/view/141908

  ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control. […] The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. […] We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. […] In our quest to clarify the role of FGFR signaling in SS pathogenesis, we uncovered an oncogenic axis that connects the FGFR pathway to the oncogenic ETS factors ETV4 and ETV5, and regulation of the DUX4 embryonic program. […] Our results show that expression of ETV4 and ETV5 is regulated by FGFR signaling at the transcriptional level. […] The findings strongly suggest that ETV4 and ETV5 are active modulators of the E2F1 pathway in SS cells, and they fit a functional model where autocrine FGF/FGFR signaling initiated by SS18-SSX activates ETV4 and ETV5. […] In summary, our findings show that ETV4 and ETV5 are downstream targets of the SS18-SSX oncoprotein and are persistently expressed in SS cells and tumors. […] Altogether, our studies have uncovered a pathogenic link between FGFR signaling, ETV4/5, and the embryonic DUX4 pathway in SS.

• #1 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  Thus, while multiple mechanisms of action for SS18::SSX have been proposed, they converge on the formation of unusually broad BAF domains that are associated with the loss of H3K27me3 and gain of active histone marks. […] SyS is genomically stable and displays few somatic mutations other than the chromosomal translocation itself, suggesting that SS18::SSX bears the prime responsibility for malignant transformation. […] This aberrant relationship between active and repressive marks in the chromatin landscape of SyS is consistent with the understood mechanisms of SS18::SSX reprogramming and likely underpins specific oncogenic processes in SyS. […] Finally, the inhibition of H3K4me3 is proposed as a novel therapeutic vulnerability in SyS.

• #1 Primary synovial sarcoma of the duodenal bulb: a case report and review of the literature – Yang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/42817/html

  In recent studies, the over-activation of IGF-1 and insulin receptor (IGF1R/InsR) was shown to alter the AKT and ERK pathways in synovial sarcoma cells. AKT and ERK activity was reduced, which in turn reduced the resistance of tumor cells to pazopanib. […] Recent studies confirmed that activation of YAP/TAZ signaling is a common pattern in SS and is functionally dependent on the SS18-SSX fusion protein, which interferes with YAP. The interference in signal transduction of TAZ through small molecule inhibitors may provide a new and effective way for the treatment of synovial sarcoma. […] The 5- and 10-year survival rates of patients with synovial sarcoma of bone tissue are 76.4% and 60.4%, respectively, which are related to tumor size, tumor grade, chemotherapy, and radiation therapy. […] Since synovial sarcoma of the digestive system is difficult to diagnose, easily misdiagnosed, has a high degree of malignancy, and few cases are seen, there is no relevant literature that reports the long-term survival rate of patients with this disease. […] In conclusion, primary synovial sarcoma of the digestive system is rare and easily misdiagnosed. We reported the first case of synovial sarcoma arising between the intestinal walls of the duodenal bulb with a concomitant SYT/SSX type of the t(X;18) translocation.

• #1

  https://link.springer.com/article/10.1007/s11864-021-00914-4

  New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. […] The concrete hypothesis that the pathogenesis of SS might mainly depend on the disruption of the balance of the complex interaction between epigenomic regulatory complexes and the consequences on gene expression opens interesting new perspectives. […] As mentioned above, the SS18-SSX fusion proteins are widely considered to be the main driver of SS pathogenesis, as their expression is sufficient to induce SS tumors in mice, and their silencing causes SS cells to revert to mesenchymal stem cell-like cells. […] There is currently no definitive theory for the pathogenesis of SS; however, the previous hypothesis shows that it could principally depend on the disruption of the balance of the complex interplay between the TrxG and PcG complexes. Therefore, a better understanding of the effects and consequences of the expression of SS18-SSX fusion proteins on the epigenomic regulators is needed.

• #2 Synovial Sarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1257131-overview

  The origin of synovial sarcoma is unclear. Its name notwithstanding, this sarcoma is not associated with synovial joints. The basis for the name synovial cell sarcoma was the similarity between cells of this tumor and primitive synoviocytes. […] A neurologic origin for this sarcoma has been suggested. In fact, there is a histologic resemblance between the neural cells of malignant peripherical nerve sheath tumor (MPNST) and the cells of synovial sarcoma. […] The (X;18)(p11;q11) translocation fuses the SYT gene from chromosome 18 to a homologous gene at Xp11 (SSX1, SSX2, or SSX4). The fusion proteins SYT-SSX1 and SYT-SSX2 are believed to function as aberrant transcriptional regulators, resulting in either activation of proto-oncogenes or inhibition of tumor suppressor genes. […] A correlation appears to exist between the histologic subtype of the tumor and either of these two fusion proteins. Biphasic tumors, containing both epithelial and spindle cell components, express the SYT-SSX1 transcript, whereas monophasic tumors with only a spindle cell component may express either transcript.

• #2 Synovial Sarcoma: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1257131-overview

  Synovial sarcoma is characterized by a specific chromosomal translocation, t(X;18)(p11;q11). This defect appears to be the underlying cause of the tumor. This specific chromosomal translocation between chromosome X and chromosome 18 has been noted in more than 90% of cases. This fusion gene is called, in genetic terms, the SYT-SSX1, SYT-SSX2, or SYT-SSX4. These terms correspond to a fusion of the SYT gene (chromosome 18) with the SSX gene (chromosome X). […] To our knowledge, the origin of this translocation has not been identified.

• #2

  https://www.orthobullets.com/pathology/8052/synovial-sarcoma

  Synovial Sarcoma is a malignant, soft tissue sarcoma caused by a t(X;18) chromosomal translocation mutation (SS18:SSX fusion protein) most commonly found near joints but rarely within the joint. […] Mechanism: mesenchymal soft tissue sarcoma with unknown cellular origin; synovial sarcoma is a misnomer due to the tumor’s microscopic resemblance to mature synovium. […] Chromosomal translocation t(X;18) is observed in more than 90% of cases. […] Translocation forms the SYT-SSX1, 2, or 4 fusion protein. […] Fusion proteins bind to BAF complex, which displaces the tumor suppressor BAF47; new BAF complex activates Sox2, which leads to tumor formation. […] Cellular origin of synovial sarcoma is unknown.

• #2 Synovial sarcoma mechanisms: a series of unfortunate events – PubMed

  https://pubmed.ncbi.nlm.nih.gov/23540685/

  Human synovial sarcoma is caused by a chromosome translocation, which fuses DNA encoding SSX to that encoding the SS18 protein. […] Kadoch and Crabtree now show that the resulting cellular transformation stems from disruption of the normal architecture and function of the human SWI/SNF (BAF) complex.

• #2 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18::SSX fusion oncoprotein. SS18::SSX associates with mammalian BAF complexes suggesting deregulation of chromatin architecture as the oncogenic driver in this tumour type. […] Our analysis revealed a continuum of epigenomic states across the cohort at fusion target genes independent of rare somatic genetic lesions. […] The number of bivalent promoters, dually marked by the repressive H3K27me3 and activating H3K4me3 marks, has strong prognostic value and outperforms tumor grade in predicting patient outcome. […] Finally, we identify SyS defining epigenomic features including H3K4me3 expansion associated with striking promoter DNA hypomethylation in which SyS displays the lowest mean methylation level of any sarcoma subtype.

• #2 Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy

  https://www.mdpi.com/2073-4409/13/20/1695

  Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. […] Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. […] SS pathogenesis is mainly driven by SS18-SSX fusion proteins playing an important role in the regulation of chromatin remodeling. The key epigenetic regulators, switch/sucrose-non-fermentable (SWI/SNF) complexes, are the members of the Trithorax-group protein (TrxG) family. […] The oncogenic SWI/SNF complexes could target PRC-repressed domains and activate them by recruiting RNA Polymerase II and initiating transcription.

• #2 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  Thus, while multiple mechanisms of action for SS18::SSX have been proposed, they converge on the formation of unusually broad BAF domains that are associated with the loss of H3K27me3 and gain of active histone marks. […] SyS is genomically stable and displays few somatic mutations other than the chromosomal translocation itself, suggesting that SS18::SSX bears the prime responsibility for malignant transformation. […] This aberrant relationship between active and repressive marks in the chromatin landscape of SyS is consistent with the understood mechanisms of SS18::SSX reprogramming and likely underpins specific oncogenic processes in SyS. […] Finally, the inhibition of H3K4me3 is proposed as a novel therapeutic vulnerability in SyS.

• #2

  https://link.springer.com/article/10.1007/s11864-021-00914-4

  New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. […] The concrete hypothesis that the pathogenesis of SS might mainly depend on the disruption of the balance of the complex interaction between epigenomic regulatory complexes and the consequences on gene expression opens interesting new perspectives. […] As mentioned above, the SS18-SSX fusion proteins are widely considered to be the main driver of SS pathogenesis, as their expression is sufficient to induce SS tumors in mice, and their silencing causes SS cells to revert to mesenchymal stem cell-like cells. […] There is currently no definitive theory for the pathogenesis of SS; however, the previous hypothesis shows that it could principally depend on the disruption of the balance of the complex interplay between the TrxG and PcG complexes. Therefore, a better understanding of the effects and consequences of the expression of SS18-SSX fusion proteins on the epigenomic regulators is needed.

• #2 The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1 | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005060

  Recent evidence implicates deregulation of polycomb function in cancer promotion. […] The integrity of the Bmi1/Ring1B interaction was therefore assessed by coimmunoprecipitating (co/IP) Bmi1 from SYT-SSX2 and pOZ vector control infectants using anti-Ring1B antibodies. […] The pronounced depletion of Bmi1 from the Bmi1/Ring1B complex by SYT-SSX2 raised the possibility that some Bmi1-mediated function related to polycomb silencing may be compromised in the presence of SYT-SSX2. […] Taken together, these results demonstrate a general loss of Bmi1-specific histone-modifying function caused by SYT-SSX2-mediated depletion of Bmi1. […] In summary, the SYT-SSX2 oncogene appears to influence gene-expression programs through its association with and subsequent antagonism of polycomb components in mesenchymal cells. This function likely constitutes part of its transforming activity in synovial sarcoma.

• #2 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  SS18::SSX competes with endogenous SS18 to incorporate into the canonical (cBAF) and non-canonical (GBAF) forms of the remodeling complex. […] Incorporation of the fusion protein into cBAF results in its degradation, which in turn increases the relative prevalence of other BAF-family complexes (polybromo-associated (PBAF) and GBAF), altering the BAF subtype balance and genomic distribution. […] The observed synthetic lethality associated with elevated prevalence of GBAF indicated a potential therapeutic vulnerability in SyS, although recent clinical trials focused on targeting BRD9 (a specific component of the GBAF complex) did not show clinical benefit. […] SS18::SSX interacts genetically and physically with numerous epigenetic regulatory proteins including the DNA binding protein ATF2, the transcriptional corepressor TLE1 and members of non-canonical polycomb group repressor complexes.

• #2

  https://www.jci.org/articles/view/141908

  ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control. […] The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. […] We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. […] In our quest to clarify the role of FGFR signaling in SS pathogenesis, we uncovered an oncogenic axis that connects the FGFR pathway to the oncogenic ETS factors ETV4 and ETV5, and regulation of the DUX4 embryonic program. […] Our results show that expression of ETV4 and ETV5 is regulated by FGFR signaling at the transcriptional level. […] The findings strongly suggest that ETV4 and ETV5 are active modulators of the E2F1 pathway in SS cells, and they fit a functional model where autocrine FGF/FGFR signaling initiated by SS18-SSX activates ETV4 and ETV5. […] In summary, our findings show that ETV4 and ETV5 are downstream targets of the SS18-SSX oncoprotein and are persistently expressed in SS cells and tumors. […] Altogether, our studies have uncovered a pathogenic link between FGFR signaling, ETV4/5, and the embryonic DUX4 pathway in SS.

• #2 Synovial sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Synovial_sarcoma

  A synovial sarcoma (also known as malignant synovioma) is a rare form of cancer which occurs primarily in the extremities of the arms or legs, often in proximity to joint capsules and tendon sheaths. […] The name „synovial sarcoma” was coined early in the 20th century, as some researchers thought that the microscopic similarity of some tumors to synovium, and its propensity to arise adjacent to joints, indicated a synovial origin; however, the actual cells from which the tumor develops are unknown and not necessarily synovial. […] Most, and perhaps all, cases of synovial sarcoma are associated with a reciprocal translocation t(x;18)(p11.2;q11.2). […] This translocation event between the SS18 gene on chromosome 18 and one of 3 SSX genes (SSX1, SSX2 and SSX4) on chromosome X causes the presence of an SS18-SSX fusion gene. […] SS18-SSX is thought to underlie synovial sarcoma pathogenesis through dysregulation of gene expression. […] There is some association between the SS18-SSX1 or SS18-SSX2 fusion type and both tumour morphology and five-year survival.

• #2

  https://www.omim.org/entry/300813

  The SYT-SSX1 form of synovial sarcoma, compared to the SYT-SSX2 form, has a significantly unfavorable prognosis (Kawai et al., 1998; Ladanyi et al., 2002). This suggests that the SYT-SSX fusion genes may influence molecular mechanisms involved in tumor growth and progression and that SYT-SSX1 has a stronger influence on these mechanisms than SYT-SSX2. […] Xie et al. (2002) used Western blot analysis on 74 fresh, fusion variant-typed tumor samples from localized synovial sarcoma and found a significant correlation between SYT-SSX1 and high expression of cyclin A1 (CCNA1; 604036) and cyclin D1 (CCND1; 168461); P = 0.003 and P = 0.025, respectively. The data suggested that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 variant is due to an accelerated tumor cell proliferation.

• #2

  https://link.springer.com/article/10.1245/s10434-017-5855-x

  The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. […] The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway. […] Metastatic potential is determined early in synovial sarcoma development and reflected by tumor molecular features.

• #2 Targeting the Pentose Phosphate Pathway for the Treatment of Synovial Sarcoma – SFA

  https://curesarcoma.org/funded-research/targeting-the-pentose-phosphate-pathway-for-the-treatment-of-synovial-sarcoma/

  As ME1 is not expressed in SS, and G6PD can be inhibited by DHEA, a novel therapeutic strategy for the treatment of SS can be developed using DHEA. […] Hence, we hypothesize that: understanding glucose and energy metabolism of Synovial Sarcoma and the mechanism of glucose withdrawal cell death, we will develop a therapy for SS based on PPP-based metabolic targets. […] Aim 1 is to characterize the mechanism of cell death caused by glucose withdrawal. This will allow us to better target SS therapeutically. Aim 2 is to determine if the transcriptional down regulation of ME1 in Synovial Sarcoma is directly or indirectly caused by the SYT-SSX translocation. […] Aim 3 is to determine the metabolic consequences of DHEA treatment in vivo in a spontaneous model of Synovial Sarcoma. This will allow us to validate our observation in a spontaneous model, and to use metabolomics to determine if there are additional targets for duel metabolic therapy in addition to G6PD inhibition. Taken together, this proposal lays the foundation for a novel therapeutic strategy for SS.

• #2 Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma | bioRxiv

  https://www.biorxiv.org/content/10.1101/2022.05.09.490894.full

  Given the high noise due to FFPE samples and the low specificity of the fusion gene identification pipelines, a rigorous filtering process was performed in the FusionCatcher, excluding banned, high common mapping reads, promiscuous genes, low bioinformatics support, adjacent, and short repeats, which were considered to be false positives and were removed before downstream analyses. […] These findings support previous data showing that the primary fusion gene SS18-SSX is the main driver of tumorigenesis in SS. […] We observed that SSC-I was significantly associated with poor survival, metastasis, had significantly highest rates of mitosis and the lowest stromal and immune scores. […] The vascularized-SS (SSC-II) cluster was characterized by better patient outcome. […] The epithelial-SS (SSC-III) was dominated by biphasic tumors and characterized by higher levels of kinase-signaling targets, innate immune cell infiltration and lower levels of proliferation and DNA repair.

• #2 Behind the FDA Approval: Afami-Cel in Synovial Sarcoma

  https://www.targetedonc.com/view/behind-the-fda-approval-afami-cel-in-synovial-sarcoma

  Afami-cel is a T-cell receptor. The way it works is that it takes a patient’s own immune cells and redirects them to the type of protein that is found in the patient’s tumor. In this particular case, the protein is called MAGE-A4. […] This form of therapy is an effective therapy for immunologically cold tumors. Synovial sarcoma sort of is a prototype of a type of cancer that has limited immune cells. Other drugs, such as checkpoint inhibitors, have been shown to be relatively ineffective. […] The fact that we can effectively stimulate the immune system with this exogenous administration of a patient’s own immune cell that has been effectively genetically engineered holds promise that this can probably be expanded to other solid tumors that express this protein. […] The standard of care for synovial sarcoma is typically surgery with or without radiation and with or without adjuvant chemotherapy, but unfortunately, 50% of patients develop metastases and, obviously in the setting of metastatic disease, the disease is no longer curable. […] Afami-cel offers a remarkable improvement upon the standard of care, so it is a promising and exciting option for our patients.

• #2 Synovial sarcoma of female urethra: a case report and review of the literature | Diagnostic Pathology | Full Text

  https://diagnosticpathology.biomedcentral.com/articles/10.1186/s13000-023-01367-z

  However, the commonly used chemotherapy regimen for SS is based on doxorubicin combined with isocyclophosphamide. […] Neoadjuvant or adjuvant radiotherapy is recommended for SS with tumours5 cm in diameter or where neurovascular structures or bone need to be preserved. […] In order to improve the efficacy of anti-tumour therapy and to reduce tissue damage, scholars have proposed targeted therapy and immunotherapy. […] The greatest advantage of targeted therapy is that it is highly selective, causes less damage to normal tissues and results in far fewer adverse effects than conventional radiotherapy and chemotherapy. […] A randomised controlled phase III study from Japan showed that the median PFS was significantly longer in the pazopanib treatment group, 24.7 weeks vs. 7.0 weeks, but did not significantly improve median OS, 15.4 months vs. 14.9 months, when receiving oral pazopanib 800 mg compared with placebo. […] There are still many more clinical studies in SS for NY-ESO-1 in the trial phase, but based on the available findings, exciting early results have been shown.

• #2 Treatment and Screen for Synovial Sarcoma | Explore Technologies

  https://techfinder.stanford.edu/technology/treatment-and-screen-synovial-sarcoma

  Researchers in Prof. Gerald Crabtree’s laboratory have identified the pathological mechanism for synovial sarcoma (SS) that could be used to develop targeted therapeutics. […] This approach aims to reverse the effects of the SS18-SSX fusion protein (the hallmark of human SS). […] The inventors discovered that SS18-SSX causes cell proliferation through a chain of events that induces Sox2 expression. […] Because this mechanism of transformation depends on only a small portion of the fusion protein, that region provides a viable foundation for therapeutic intervention.

• #2 Synovial Sarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/synovial-sarcoma/

  Synovial sarcoma (SS) is a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation. SS is characterized by a specific SS18-SSX1/2/4 fusion gene. […] SS cells are dependent on SS18-SSX expression to maintain their transformed phenotype. Conditional expression of SS18-SSX induces SSs in genetically engineered mouse models, supporting its function as an oncogene when expressed in permissive mesenchymal progenitor cells. Additionally, SS18-SSX1 has been shown to transform primary cell lines. Recent evidence suggests that the SS18-SSX fusion protein disrupts epigenetic control and blocks mesenchymal differentiation by complementary mechanisms including competitive binding with, and displacement of, native SS18 in the SWI/SNF chromatin-remodeling complex, inducing dependency on BRD9-containing alternative SWI/SNF complexes (ncBAF complexes) and colocalizing with factors such as the ATF2 transcription factor, TLE1 to repress ATF2 target genes, and the KDM2B lysine demethylase at unmethylated CpG islands to reactivate repressed genes.

• #2 Primary synovial sarcoma of the duodenal bulb: a case report and review of the literature – Yang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/42817/html

  In recent studies, the over-activation of IGF-1 and insulin receptor (IGF1R/InsR) was shown to alter the AKT and ERK pathways in synovial sarcoma cells. AKT and ERK activity was reduced, which in turn reduced the resistance of tumor cells to pazopanib. […] Recent studies confirmed that activation of YAP/TAZ signaling is a common pattern in SS and is functionally dependent on the SS18-SSX fusion protein, which interferes with YAP. The interference in signal transduction of TAZ through small molecule inhibitors may provide a new and effective way for the treatment of synovial sarcoma. […] The 5- and 10-year survival rates of patients with synovial sarcoma of bone tissue are 76.4% and 60.4%, respectively, which are related to tumor size, tumor grade, chemotherapy, and radiation therapy. […] Since synovial sarcoma of the digestive system is difficult to diagnose, easily misdiagnosed, has a high degree of malignancy, and few cases are seen, there is no relevant literature that reports the long-term survival rate of patients with this disease. […] In conclusion, primary synovial sarcoma of the digestive system is rare and easily misdiagnosed. We reported the first case of synovial sarcoma arising between the intestinal walls of the duodenal bulb with a concomitant SYT/SSX type of the t(X;18) translocation.

• #3 Synovial sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Synovial_sarcoma

  A synovial sarcoma (also known as malignant synovioma) is a rare form of cancer which occurs primarily in the extremities of the arms or legs, often in proximity to joint capsules and tendon sheaths. […] The name „synovial sarcoma” was coined early in the 20th century, as some researchers thought that the microscopic similarity of some tumors to synovium, and its propensity to arise adjacent to joints, indicated a synovial origin; however, the actual cells from which the tumor develops are unknown and not necessarily synovial. […] Most, and perhaps all, cases of synovial sarcoma are associated with a reciprocal translocation t(x;18)(p11.2;q11.2). […] This translocation event between the SS18 gene on chromosome 18 and one of 3 SSX genes (SSX1, SSX2 and SSX4) on chromosome X causes the presence of an SS18-SSX fusion gene. […] SS18-SSX is thought to underlie synovial sarcoma pathogenesis through dysregulation of gene expression. […] There is some association between the SS18-SSX1 or SS18-SSX2 fusion type and both tumour morphology and five-year survival.

• #3 Synovial Sarcoma of the Extremities: A Literature Review

  https://www.mdpi.com/2076-3417/11/16/7407

  Synovial sarcoma (SS) is a rare and highly malignant tumor and a type of soft tissue sarcoma (STS), for which survival has not improved significantly in recent years. […] Synovial sarcoma is characterized by the presence of the pathognomonic t (X; 18) (p11.2; q11.2) translocation, involving a fusion of the SS18 (formerly SYT) gene on chromosome 18 to one of the synovial sarcoma X (SSX) genes on chromosome X (usually SSX1 or SSX2), which is seen in more than 90% of SSs and results in the formation of SS18-SSX fusion oncogenes. […] The origin of the synovial sarcoma comes not from the articular synovial tissue. […] The certain diagnosis of synovial sarcoma remains a challenge and the recognition of the disease should be based upon a combination of findings, including traditional morphology, detection of the chromosomal t (X; 18) translocation and a panel of immunohistochemical markers.

• #3 Synovial Sarcoma | Cancer Genetics Web

  http://www.cancerindex.org/geneweb/X200302.htm

  A S18-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is characteristic of nearly all synovial sarcomas. This translocation fuses the SS18T (SYT) gene from chromosome 18 to one of three homologous genes at Xp11, SSX1, SSX2 or SSX4. […] 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. […] 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.

• #3

  https://www.orthobullets.com/pathology/8052/synovial-sarcoma

  Synovial Sarcoma is a malignant, soft tissue sarcoma caused by a t(X;18) chromosomal translocation mutation (SS18:SSX fusion protein) most commonly found near joints but rarely within the joint. […] Mechanism: mesenchymal soft tissue sarcoma with unknown cellular origin; synovial sarcoma is a misnomer due to the tumor’s microscopic resemblance to mature synovium. […] Chromosomal translocation t(X;18) is observed in more than 90% of cases. […] Translocation forms the SYT-SSX1, 2, or 4 fusion protein. […] Fusion proteins bind to BAF complex, which displaces the tumor suppressor BAF47; new BAF complex activates Sox2, which leads to tumor formation. […] Cellular origin of synovial sarcoma is unknown.

• #3 Synovial Sarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/synovial-sarcoma/

  Synovial sarcoma (SS) is a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation. SS is characterized by a specific SS18-SSX1/2/4 fusion gene. […] SS cells are dependent on SS18-SSX expression to maintain their transformed phenotype. Conditional expression of SS18-SSX induces SSs in genetically engineered mouse models, supporting its function as an oncogene when expressed in permissive mesenchymal progenitor cells. Additionally, SS18-SSX1 has been shown to transform primary cell lines. Recent evidence suggests that the SS18-SSX fusion protein disrupts epigenetic control and blocks mesenchymal differentiation by complementary mechanisms including competitive binding with, and displacement of, native SS18 in the SWI/SNF chromatin-remodeling complex, inducing dependency on BRD9-containing alternative SWI/SNF complexes (ncBAF complexes) and colocalizing with factors such as the ATF2 transcription factor, TLE1 to repress ATF2 target genes, and the KDM2B lysine demethylase at unmethylated CpG islands to reactivate repressed genes.

• #3

  https://link.springer.com/article/10.1007/s11864-021-00914-4

  New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. […] The concrete hypothesis that the pathogenesis of SS might mainly depend on the disruption of the balance of the complex interaction between epigenomic regulatory complexes and the consequences on gene expression opens interesting new perspectives. […] As mentioned above, the SS18-SSX fusion proteins are widely considered to be the main driver of SS pathogenesis, as their expression is sufficient to induce SS tumors in mice, and their silencing causes SS cells to revert to mesenchymal stem cell-like cells. […] There is currently no definitive theory for the pathogenesis of SS; however, the previous hypothesis shows that it could principally depend on the disruption of the balance of the complex interplay between the TrxG and PcG complexes. Therefore, a better understanding of the effects and consequences of the expression of SS18-SSX fusion proteins on the epigenomic regulators is needed.

• #3 The Synovial Sarcoma-Associated SYT-SSX2 Oncogene Antagonizes the Polycomb Complex Protein Bmi1 | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005060

  This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. […] The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. […] This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. […] These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.

• #3 Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy

  https://www.mdpi.com/2073-4409/13/20/1695

  Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. […] Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. […] SS pathogenesis is mainly driven by SS18-SSX fusion proteins playing an important role in the regulation of chromatin remodeling. The key epigenetic regulators, switch/sucrose-non-fermentable (SWI/SNF) complexes, are the members of the Trithorax-group protein (TrxG) family. […] The oncogenic SWI/SNF complexes could target PRC-repressed domains and activate them by recruiting RNA Polymerase II and initiating transcription.

• #3 Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma | bioRxiv

  https://www.biorxiv.org/content/10.1101/2022.05.09.490894.full

  Synovial sarcomas (SS) are malignant mesenchymal tumors characterized by the SS18-SSX fusion gene, which drives tumorigenesis by altering the composition of the BAF complex. […] The chimeric oncoprotein SS18-SSX hijacks the BAF complex and consequently reprograms chromatin architecture to promote sarcomagenesis, essentially gaining stem-cell-like properties. […] Our findings explain broad concepts in SS biology and imply that the BAF composition at the start of the tumorigenesis (i.e. the cellular lineage) may determine the SS subtype, providing a rationale for individualized treatment strategies. […] The unfavorable therapeutic effectiveness in the metastatic setting strongly motivates new therapies and a thorough understanding of the SS landscape at the transcriptome, genome, and proteome levels.

• #3 Synovial sarcoma : translating gene expression into patient care – UBC Library Open Collections

  https://open.library.ubc.ca/soa/cIRcle/collections/ubctheses/24/items/1.0066337

  Synovial sarcoma is a soft tissue tumor defined by the presence of t(X;18)(p11.2;q11.2), fusing the SYT (SS18) gene on chromosome 18 and one of three SSX genes on chromosome X. T(X;18) results in production of a fusion protein (SYT-SSX) that is thought to underlie synovial sarcoma pathogenesis through aberrant targeting of both activating (trithorax, SWI/SNF) and repressing (Polycomb) transcription factors when expressed in a stem or progenitor-like cellular background. […] I describe preclinical studies that demonstrate the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits proliferation of synovial sarcoma by inducing apoptosis and that this is associated with degradation of multiple receptor tyrosine kinases and disruption of the SYT-SSX–catenin interaction.

• #3 SS18F – Overview: Synovial Sarcoma (SS), 18q11.2 (SS18 or SYT) Rearrangement, FISH, Tissue

  https://www.mayocliniclabs.com/test-catalog/overview/35303

  Identification of the SS18-SSX1 fusion is associated with an unfavorable outcome with significantly shorter overall survival when compared to the SS18-SSX2 fusion. […] In these cases, FISH testing can be used to identify SS18 gene rearrangements in these tumors, which supports the diagnosis of SS. […] A positive result suggests rearrangement of the SS18 (SYT) gene region at 18q11.2 and supports the diagnosis of synovial sarcoma (SS). […] This test is not approved by the US Food and Drug Administration and is best used as an adjunct to existing clinical and pathologic information. […] Rearrangement of SS18 was identified in all 14 SS specimens with 10 exhibiting the expected signal pattern and 4 with an atypical signal pattern.

• #3

  https://link.springer.com/article/10.1245/s10434-017-5855-x

  The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. […] The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway. […] Metastatic potential is determined early in synovial sarcoma development and reflected by tumor molecular features.

• #3 Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma | Nature Medicine

  https://www.nature.com/articles/s41591-020-01212-6

  Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. […] Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. […] Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

• #3 Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.05.14.594262v1.full-text

  Thus, while multiple mechanisms of action for SS18::SSX have been proposed, they converge on the formation of unusually broad BAF domains that are associated with the loss of H3K27me3 and gain of active histone marks. […] SyS is genomically stable and displays few somatic mutations other than the chromosomal translocation itself, suggesting that SS18::SSX bears the prime responsibility for malignant transformation. […] This aberrant relationship between active and repressive marks in the chromatin landscape of SyS is consistent with the understood mechanisms of SS18::SSX reprogramming and likely underpins specific oncogenic processes in SyS. […] Finally, the inhibition of H3K4me3 is proposed as a novel therapeutic vulnerability in SyS.

• #3 An unusual case of primary pulmonary synovial sarcoma | The Egyptian Journal of Bronchology | Full Text

  https://ejb.springeropen.com/articles/10.1186/s43168-024-00349-z

  Synovial sarcoma is characterized by a specific chromosomal translocation producing SS18SSX 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. Cytogenetic studies of synovial sarcomas have revealed the chromosomal translocation t (x; 18) (p11; q11). This translocation fused the SYT gene from chromosome 18 to either of two homologous genes at Xp11, SSX1 or SSX2. […] Multimodality treatment including wide excision, chemotherapy and radiotherapy is the mainstay of therapy. Wherever feasible, wide surgical resection with tumour-free margins remains the preferred modality of treatment followed by chemotherapy and/or radiotherapy. […] There is a serious need for an ideal therapeutic agent in SS that is more effective and less toxic. Several novel potential therapeutic targets under research are SS18SSX fusion oncogene, epidermal growth factor receptor and vascular endothelial growth factor receptors that are the future hope in treatment of synovial sarcoma.

• #4 Synovial Sarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/synovial-sarcoma/

  Synovial sarcoma (SS) is a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation. SS is characterized by a specific SS18-SSX1/2/4 fusion gene. […] SS cells are dependent on SS18-SSX expression to maintain their transformed phenotype. Conditional expression of SS18-SSX induces SSs in genetically engineered mouse models, supporting its function as an oncogene when expressed in permissive mesenchymal progenitor cells. Additionally, SS18-SSX1 has been shown to transform primary cell lines. Recent evidence suggests that the SS18-SSX fusion protein disrupts epigenetic control and blocks mesenchymal differentiation by complementary mechanisms including competitive binding with, and displacement of, native SS18 in the SWI/SNF chromatin-remodeling complex, inducing dependency on BRD9-containing alternative SWI/SNF complexes (ncBAF complexes) and colocalizing with factors such as the ATF2 transcription factor, TLE1 to repress ATF2 target genes, and the KDM2B lysine demethylase at unmethylated CpG islands to reactivate repressed genes.

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