108 research outputs found
Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion
In recent years, undifferentiated small round cell sarcomas (USRCSs) have been divided into a variety of new, rare, sarcoma subtypes, including the group of Ewing-like sarcomas, which have the morphological appearance of Ewing sarcomas, but carry CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classic EWSR1-ETS gene fusion. Using high-throughput RNA-sequencing (RNA-seq) analyses, we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by reverse transcription polymerase chain reaction, long-range polymerase chain reaction, and fluorescence in situ hybridization. In vitro, we showed that the cells expressing the gene fusion were morphologically distinct and had enhanced oncogenic potential as compared with control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1-positive tumours. Moreover, these analyses indicated enhanced NTRK1 expression in CRTC1-SS18-positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCSs with unique gene signatures, and may be of therapeutic relevance. Copyright Β© 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
Prognostic value of SS18βSSX fusion type in synovial sarcoma; systematic review and meta-analysis
Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling
Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. In this study, we have used genome-wide expression profiling to categorise synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas (MFHs). Following hierarchical clustering analysis of the expression data, the best match between tumour clusters and conventional diagnosis was observed for synovial sarcomas. Eight of nine synovial sarcomas examined formed a cluster that was characterised by higher expression of a set of 48 genes. In contrast, sarcomas conventionally classified as leiomyosarcomas and MFHs did not match the clusters defined by hierarchical clustering analysis. One major cluster contained a mixture of both leiomyosarcomas and MFHs and was defined by the lower expression of a set of 202 genes. A cluster containing a subgroup of MFHs was also detected. These results may have implications for the classification of soft tissue sarcomas, and are consistent with the view that sarcomas conventionally defined as MFHs do not represent a separate diagnostic category. (C) 2003 Cancer Research UK
Ki-67 is strongly prognostic in synovial sarcoma: analysis based on 86 patients from the Scandinavian Sarcoma Group Register
Targeted degradation of BRD9 reverses oncogenic gene expression in 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
SS18 Together with Animal-Specific Factors Defines Human BAF-Type SWI/SNF Complexes
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Primary pleuropulmonary and mediastinal synovial sarcoma: a clinicopathologic and molecular study of 26 genetically confirmed cases in the largest institution of southwest China
Synovial sarcoma : a Scandinavian sarcoma group project
Synovial sarcoma accounts for 5 to 10 % of all soft tissue sarcomas. More
than 90 % are found in the extremities or trunk wall. Characteristic for
synovial sarcoma is the translocation t(X; 18) (p11.2;q11.2). Cloning of
the breakpoints of this translocation revealed fusion of two novel genes,
SYT and SSX. The SYT gene, located on chromosome 18, is fused with one of
three closely related genes; SSX1, SSX2 or SSX4 located on the X
chromosome.
The long term survival rates have continuously improved and have at best
been reported to around 50 %. However, since almost no population based
studies on synovial sarcoma have been reported, these improvements may be
due to differences in patient selection due to a changes in referral
practice. This project was based on a consecutive series of synovial
sarcoma patients from the Scandinavian Sarcoma Group Register acquired
during a 9-year period. Only surgically treated patients without
metastases at diagnosis were included in the prognostic analyses. The
tumors were defined clinically, histopathologically, molecular and
cytogenetically and these features were related to clinical course.
34 of 104 patients developed metastases. The overall 5 and 7 years
survival rates were 0.76 (95% CI 0.66-0.83) and 0.69 (0.58-0.78),
respectively. Large tumor size and amputation were significantly
associated with impaired metastasis free survival. In addition, patients
with local recurrence had a higher risk for metastases following the
local event.
Histologically, all were high grade lesions, 74 Grade III and 30 IV.
Kaplan-Meier estimates of metastasis-free survival at 5 years were 83%
(95% CI 72-92%) for patients with Grade III tumors versus 31% (95% CI
13-5 1%) for Grade IV. Histologic grading conveyed more prognostic
information than any single histologic factor.
Immunostaining with anti-Ki-67 antibodies (MIB1) and p53 based on
formalin-fixed paraffinembedded material from 86 patients revealed that
MIB1 > 10% was associated with poorer metastasis-free survival but p53
was not.
Type of fusion transcripts (SYT-SSX1 or SYT-SSX2) and Ki-67 were assessed
in fresh frozen tissue from 33 patients. The 5-year metastasis-free
survival for patients with SYT-SSX1 was 42% versus 89% for those with
SYT-SSX2. The hazard ratio for metastasis associated with the SYT-SSX1
fusion transcripts was 7 (95% CI 1.5-36, log-rank P=0.004). There was a
significant association between SYT-SSX1 and high tumor proliferation
rate.
Comparative Genomic Hybridization revealed DNA sequence copy number
changes in 35 of 69 tumor specimens. The frequency of aberrations/ tumor
were higher in monophasic tumors than in biphasic. Gains of chromosome 8
were associated with large tumors (>5 cm). There was no obvious
association between secondary aberrations and clinical outcome.
In conclusion, large tumor size, local recurrence, histologic Grade IV,
MIB1 index > 10 and possibly SYT-SSX1 fusion transcript were associated
with impaired clinical outcome
Fine-needle aspiration of synovial sarcoma: Criteria for diagnosis: Retrospective reexamination of 37 cases, including ancillary diagnostics. A Scandinavian sarcoma group study.
Multicolor fluorescence in situ hybridization analysis of a synovial sarcoma of the larynx with a t(X;18)(p11.2;q11.2) and trisomies 2 and 8
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