**4. Synovial sarcoma**

Synovial sarcoma (SyS) is a rare malignancy of soft tissue near the joints that occurs in patients of all ages but is particularly common in children and young adults. Synovial sarcoma accounts for 10% of soft tissue malignancies diagnosed annually [69]. The incidence of this disease has increased over the past three decades, while survival rates (∼56%) have remained stagnant [69, 70]. Treatment of this disease consists of radical surgical resection, radiotherapy, and adjuvant chemotherapy, which offers a chance of cure in localized disease. However, the disease is prone to relapse, and metastases are common and almost always fatal [70].

Synovial sarcoma is associated with the occurrence of a chromosomal rearrangement, t(X;18) [71]. This aberration results in the formation of a fusion gene involving SS18 (also known as SYT) and one of three related genes: SSX1, SSX2, or SSX4. The presence of an SS18-SSX fusion gene is the characteristic genomic abnormality associated with the development of Synovial sarcoma [71–73]. Similar to Ewing sarcoma, Synovial sarcoma is characterized by low somatic mutation rates and no chromosomal aberrations other than the pathognomonic fusion [74, 75]. Some genes are mutated in more than 5% of Synovial sarcoma cases, including TP53, PTEN, CTNNB1, and APC [74]. Histologically, Synovial sarcoma shows a unique pattern with variable mesenchymal and epithelial components [74]. Expression of an SS18-SSX fusion leads to transformation of cultured fibroblasts and development of high-penetrance synovial sarcoma-like disease in mice when expressed in muscle progenitor cells [76, 77]. On the other hand, knockdown of the fusion protein in Synovial sarcoma cells results in the death of these cells [78].

SS18-SSX fusions do not act as transcription factors because neither SS18 nor the SSX proteins contain DNA-binding domains. Instead, they function as transcriptional regulators, aberrant chromatin regulators that drive oncogenesis by deregulating epigenetic processes and gene expression [79, 80]. SS18 is a member of the BAF complex (also known as the SWI/SNF complex) that directly interacts with the catalytic subunit of this nucleosome remodeling complex, BRM [81, 82]. BAF complexes promote gene activation through nucleosome remodeling that opens DNA for access by transcription factors and the transcription machinery. SSX proteins, on the other hand, have been shown to colocalize with Polycomb group proteins, which tend to function as gene repressors [83]. Current models suggest two potentially competing mechanisms of transforming activity in synovial sarcomas: SS18-SSX displaces wild-type SS18 and BAF47 (also known as SMARCB1, SNF5, or INI1) from the BAF complex, which may then drive Sox2-mediated proliferation/differentiation [79]. Alternatively, there is evidence that SS18-SSX can directly recruit Polycomb repressor complex 2 (PRC2) and Histone-Deacetylases (HDAC) to ATF2 targets, silencing transcription at these sites [84]; other studies have implicated SS18-SSX fusion genes in epigenetic regulation and modification of target genes [85, 86]. Treatment with a selective inhibitor of the histone methyltransferase EZH2, the enzymatic component

of the PRC2, reverses gene expression of synovial sarcomas and leads to growth inhibition and cell death in SS18-SSX-positive cells [87].

Most recently, two studies have further elucidated mechanisms underlying the retargeting of SS18-SSX-containing BAF complexes. Using CRISPR/Cas9-mediated epitope tagging, Banito et al. were able to investigate SS18-SSX1 occupancy and its effects on gene expression genome-wide. They observed that SS18-SSX1 is recruited to unmethylated CpG-rich sequences on DNA through interaction with lysine demethylase 2B (KDM2B), a core component of the non-canonical PRC1.1, also known as the BCOR complex. Recruitment of SS18-SSX to these PRC1.1 targets results in abnormal induction of genes that constitute a gene signature of Synovial sarcoma, including transcription factors associated with neurogenesis and development [88]. Second, McBride et al. have shown that SS18-SSX targets BAF complexes in bivalent chromatin regions to genes marked by H3K4me3 and H3K27me3, repressing PRC2 and abnormally activating a gene program essential for Synovial sarcoma survival. Loss of SS18-SSX results in decreased binding of the BAF complex to genes that depend on the fusion for their continued expression decreased chromatin accessibility at these sites, and mesenchymal differentiation [89].
