Epigenetic Targets in Synovial Sarcoma: A Mini-Review

Abstract

Synovial Sarcomas (SS) are a type of Soft Tissue Sarcoma (STS) and represent 8–10% of all STS cases. Although SS can arise at any age, it typically affects younger individuals aged 15–35 and is therefore part of both pediatric and adult clinical practices. SS occurs primarily in the limbs, often near joints, but can present anywhere. It is characterized by the recurrent pathognomonic chromosomal translocation t(X;18)(p11.2;q11.2) that most frequently fuses SSX1 or SSX2 genes with SS18. This leads to the expression of the SS18-SSX fusion protein, which causes disturbances in several interacting multiprotein complexes such as the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, also known as the BAF complex and the Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). Furthermore, this promotes widespread epigenetic rewiring, leading to aberrant gene expression that drives the pathogenesis of SS. Good prognoses are characterized predominantly by small tumor size and young patient age. Whereas, high tumor grade and an increased genomic complexity of the tumor constitute poor prognostic factors. The current therapeutic strategy relies on chemotherapy and radiotherapy, the latter of which can lead to chronic side effects for pediatric patients. We will focus on the known roles of SWI/SNF, PRC1, and PRC2 as the main effectors of the SS18-SSX-mediated genome modifications and we present existing biological rationale for potential therapeutic targets and treatment strategies.

The chromatin landscape of primary synovial sarcoma organoids is linked to specific epigenetic mechanisms and dependencies

“…SS18 is a component of the mammalian chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF also known as BRG1/BRM-associated factor, BAF) ( Wang et al, 1996a , 1996b ; Kadoch & Crabtree, 2013 ), which facilitates transcription by increasing chromatin accessibility at promoter and enhancer regions. In contrast, SSX1/2 belongs to a family of transcriptional repressors that co-localize with polycomb group proteins (PcG), including BMI1 and RING1B ( Hale et al, 2019 ; Johansen & Gjerstorff, 2020 ). The two constituents of the fusion protein are thus associated with opposing effects on chromatin regulation and the integration of their activities appears to provide the key toward establishing the oncogenic signaling network that generates SyS.…”

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

“…SS is the most common non-rhabdomyosarcoma STS in adolescents and young adults (Hale et al, 2019). Conversely to the adult forms, pediatric SS are rarely metastatic at diagnosis (Ferrari et al, 2012a) but has a predisposition to metastasize resulting in 5-years disease free survival or 60% after the first surgery of localized tumor followed by first-line chemotherapy with alkylating agents (Ferrari et al, 2012b;Sultan et al, 2009).…”

“…In two third of cases SS is characterized by the chromosomal translocation t(X;18) as the only cytogenetic abnormality, which encodes for the fusion oncoprotein SS18/SSX1 considered the driver of malignancy (Haldar et al, 2007;Naka et al, 2010). Other fusion partners are SSX2 in one third and more rarely SSX4 (as reviewed by Hale et al, 2019). SS18 does not bind DNA but works as a co-activator of transcription by interacting with the SWI/SNF complex to control and drive the expression of a number of gene pathways involved in stemness, cell differentiation, and cell cycle progression (Middeljans et al, 2012).…”

The new horizon of liquid biopsy in sarcoma: the potential utility of circulating tumor nucleic acids

“…Therefore, the SYT-SSX fusion gene may not be a reliable circulating biomarker and further research is needed in SS patients. Other than translocation, SSs are mutationally quiet [154].…”