SS18-SSX fusion

Our study identifies SUMO2 as a selective dependency in synovial sarcoma. We demonstrate that the SUMO2/3 inhibitor TAK-981 impairs sarcomagenesis and reverses the SS18-SSX fusion-driven oncotranscriptome. Our study indicates that SUMO2 inhibition may be an attractive therapeutic option in synovial sarcoma.

Atypical SS18-break apart FISH pattern with loss of green signal should be interpreted as a peculiar unbalanced rearrangement of the SS18 gene and subsequent SS18-SSX fusion (IHC or/and NGS) test should be recommended in such cases. Reseach are partially supported by grant of the The National Centre for Research and Development no. GOSPOSTRATEG-VI/0016/2021.

KRT8 was identified as a key component for epithelial differentiation in biphasic tumors, potentially controlled by OVOL1 regulation. Our findings explain the histological grounds for SS classification and indicate that a significantly larger proportion of patients have high risk tumors (corresponding to SS subtype I) than previously believed.

Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.

Strong and diffuse SSX immunoreactivity was also seen in epithelioid sclerosing osteosarcoma harboring EWSR1::SSX1 fusion, while several sarcomas and melanocytic tumors including cellular blue nevus (5/7, 71%) revealed focal to diffuse, mostly weak to intermediate SSX staining. The SS18-SSX and SSX IHC is a useful tool for synovial sarcoma differential diagnosis, but unusual immunophenotype should trigger molecular genetic testing.

IHC and molecular tests are needed for definitive diagnosis. Compared with current commonly used IHC markers, SS18-SSX fusion antibody has better sensitivity to PSSL, which could be used as an alternative for FISH, reverse transcription-polymerase chain reaction or next generation sequencing in the diagnosis of PSSL.

This review provides an overview of the epidemiology and characteristics of SS in children and adults, as well as the patient journey from diagnosis to treatment. Current and future management strategies, focusing particularly on the potential of immunotherapies to improve clinical outcomes, are also summarized.

Oncoprotein expression is induced in 8-week old mice by administration of tamoxifen (which enables CreERT2 to enter the nucleus)... This new mouse model of synovial sarcoma closely recapitulates human disease as assessed by tumor location, gene expression, diagnostic markers, and histomorphology, identifying a subset of Hic1+ mesenchymal progenitor cells as permissive cells of origin for this sarcoma. The robustness and predictability of the tumor formation in this model opens a unique opportunity to test novel compounds for their therapeutic potential in synovial sarcoma.

SySa is a tumor which may benefit from YAP1 inhibition. Combining the YAP1 inhibitor verteporfin with pazopanib led to stabilization of tumors in our in vivo experiment, but was poorly tolerated. Further investigations in this and other models are needed to evaluate whether dose adjustments or other YAP1 inhibitors might be less toxic and/or more effective.

Preliminary findings from CFT8634-1101 indicate that CFT8634 demonstrated favorable tolerability and safety at early dose levels. Updated data to be presented at the conference.

In our study, the patients more commonly presented with large tumors (>5cm) in the extremity and monophasic histology, regardless of their ethnicity. Non-Hispanic patients more often had poorly differentiated tumors, metastatic disease at diagnosis, and a trend toward worse mOS. This study had limited power due to the limited number of patients, and further studies are needed to identify the presence of disease-related differences in these populations.

Comparative analysis of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 expression between the SySa cases (n=56) and the entire MASTER cohort (n=3,023) revealed significant differences for SSTR2, SSTR4, and SSTR5, with top 10% expression in 13, 31, and 22 patients, respectively. Conclusions Our study demonstrates the utility of broad molecular profiling in patients with advanced SySa for identifying subgroups of patients, whose molecular profiles may inform the design of future clinical trials.

Despite adjuvant therapies, these tumours have dismal outcomes, especially in large-sized tumours. CIC::DUX4-positive sarcomas need to be differentiated from their histopathological mimics, in view of significant treatment-related implications.

Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

Disruption of BAF complex assembly affected the coregulation of YAP1 and β-catenin, indicating that this chromatin remodeling complex plays a crucial role for interdependent YAP1 and β-catenin activation in SySa cells. Implications: This study provides deeper insights into SySa tumor biology demonstrating a mutual dependence between YAP1/TAZ and β-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.

Despite adjuvant therapies, these tumors have dismal outcomes, especially in large-sized tumors. CIC::DUX4-positive sarcomas need to be differentiated from their histopathological mimics, including ES, in view of significant treatment-related implications.

Additionally, FISH analysis of the EWSR-1 gene in nine SS cases demonstrated aberrant signalling in three cases that were recognized as a monoallelic loss of EWSR-1 (1/9), an amplification of EWSR-1 (1/9) and a translocation of EWSR-1 (1/9). In conclusion, SS18-SSX fusion gene sequencing is obligatory for a precise diagnosis of SS when dealing with a confusing immunophenotype and atypical or aberrant FISH signalling for SS18 and EWSR-1 detection.

We will analyze the different conditional SyS mouse models that, after combination with some of the few other recurrent alterations, such as gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1, have provided additional insight into the mechanisms of synovial sarcomagenesis. The recent advancements in the understanding of SyS biology and improvements in preclinical modeling pave the way to the development of new epigenetic drugs and immunotherapeutic approaches conducive to new treatment options.

Certain clinicoradiological, histopathological features, absent EWSR1 rearrangement and BCOR, SATB2, and TLE1 immunoexpression are useful for triaging these tumors for molecular testing. A review of the literature on these ultra-rare tumors, including their diagnostic mimics is presented.

In functional knockdown data, repression of SS18::SSX in synovial sarcoma cell lines is associated with reduced TRPS1 transcript levels, further supporting a model whereby TRPS1 expression is mediated, at least in part, by the SS18-SSX fusion oncoprotein. Knowledge of TRPS1 expression in synovial sarcoma may help avoid potential diagnostic pitfalls in the immunohistochemical workup of tumors.

We report here the most common genes altered on molecular profiles for two large cohorts of SS patients. The prevalence of pathogenic DDR mutation in our cohort (9%) suggests that constitutional defects in this pathway may be associated with SS. We found higher rates of positive HRD genes in the UM-Sylvester cohort, and we hypothesize that has a correlation with the specifics of our population, given the high frequency of Hispanic patients.

Adamantinomas with spindle cell morphology display overlapping histopathologic and immunohistochemical features with SS. An index of suspicion, tibial location, certain radiologic features, and application of immunostains are useful in diagnosing an adamantinoma. In cases suspicious for intraosseous SS, molecular testing for t(X;18) translocation is necessary in order to avoid an underdiagnosis of adamantinoma.

Adamantinomas with spindle cell morphology display overlapping histopathologic and immunohistochemical features with SS. An index of suspicion, tibial location, certain radiologic features, and application of immunostains are useful in diagnosing an adamantinoma. In cases suspicious for intraosseous SS, molecular testing for t(X;18) translocation is necessary in order to avoid an underdiagnosis of adamantinoma.

We performed integrative drug screening using eight SS cell lines, including NCC-SS5-C1 cells, and examined the response spectrum of existing anticancer agents. We conclude that NCC-SS5-C1 is a useful resource for studying SS.

In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies.

Perturbations of either SS18-SSX LLPS or SS18-SSX's binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.

We summarize, here, studies addressing the role of HDACs in FP-sarcoma pathobiology and HDACi-based rational drug combinations. Finally, we discuss the opportunity of exploiting drug inhibitory profile and expression/function of specific HDAC isoenzymes to harness the full therapeutic potential of HDACis in these sarcoma histotypes.

Primary synovial sarcoma of the stomach is rare and only 47 cases have been reported in the English literature to date. The maximum diameter of the lesion of our case was 6 mm which is the smallest among them.

The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.

Our series highlights the utility of SS18-SSX fusion-specific and SSX C-terminus antibodies to support the diagnosis of SS, Adjustment chemotherapy was associated with improved prognosis in this series.

Statistically, the cases with moderate or severe degree of DR showed poorer prognosis than those with no or mild DR (local recurrence: P = 0.0059, distant metastasis: P = 0.0002, tumor death: P = 0.0382). The findings of the study suggest that the DR of synovial sarcoma could be an important prognostic factor.

Resection with laparoscopic endoscopic cooperative surgery (LECS), which has not been reported before, was effective for small synovial sarcomas that could not be confirmed laparoscopically. With the combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (CLEAN-NET) procedure, it was possible to excise the tumor with the minimum excision range of the gastric serosa without opening the stomach.