Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1.
Ontology highlight
ABSTRACT:
SUBMITTER: Nicholas TR
PROVIDER: S-EPMC8364332 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hepatocellular carcinoma (HCC) is one of the most prevalent malignant neoplasms with high relapse and mortality rate. It is of great importance to identify novel and effective molecular markers to predict prognosis for the treatment of HCC. The Ewing sarcoma breakpoint region 1 (EWSR1) gene is well known to fuse with various partner genes and involved in promoting the development of multiple sarcomas, especially the Ewing sarcoma family of tumors. Nevertheless, seldom studies have focused on the role of EWSR1 in cancers of epithelial origin, let alone in HCC. In the current study, the transcriptional and clinical data of EWSR1 in HCC patients were obtained from TCGA and GEO databases, as well as 124 cases from the department of Pathology of Sichuan Jianyang People's Hospital. Kaplan-Meier and Cox regression analysis were used to assess patient prognosis. EWSR1 mRNA levels were significantly upregulated in HCC tissues than in normal liver tissues (P < 0.001). The TCGA database analysis showed upregulation of EWSR1 was associated with histological grade, pathologic T stage and death, in addition to that, the T staging, N staging, TNM staging, Ki67, AFP expression were extremely higher in the EWSR1 over-expression group in our cohort. Univariate and multivariate Cox hazard regression analysis results revealed that EWSR1 was an independent prognostic factor for OS in HCC, and bioinformatics analysis showed RNA splicing process represented the major function and pathway. In conclusion, our data showed EWSR1 could serve as a novel promising prognostic biomarker for HCC patients.Abbreviations: AFP, Alpha-fetoprotein; CCL14, C-C motif chemokine ligand 14; CK19, Cytokeratin 19; CI, coefficient interval; COL1A1, Collagen 1A1; DFS, Disease-free Survival; EWSR1, Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1; FLI1, Friend leukemia virus integration 1; GEO, Gene Expression Omnibus; GO, Gene Ontology; HCC, Hepatocellular carcinoma; HR, Hazard ratio; KEGG, Kyoto Encyclopedia of Genes and Genomes; mRNA, messenger Ribonucleic Acid; N, nodule; OS, Overall survival; PPI, Protein-Protein Interaction analysis; RNA, Ribonucleic Acid; SD, Standard Deviation; TCGA, The Cancer Genome Atlas; T, tumor; TNM, tumor-nodule-metastasis.
| S-EPMC8806985 | biostudies-literature
Project description:Chromosomal translocations between the EWS gene and members of the ETS gene family are characteristic molecular features of the Ewing sarcoma. The most common translocation t(11;22)(q24;q12) fuses the EWS gene to FLI1, and is present in 85-90% of Ewing sarcomas. In the present study, a specifically designed multiplex long-range PCR assay was applied to amplify genomic EWS-FLI1 fusion sites from as little as 100 ng template DNA. Characterization of the EWS-FLI1 fusion sites of 42 pediatric and young adult Ewing sarcoma patients and seven cell lines revealed a clustering in the 5' region of the EWS-breakpoint cluster region (BCR), in contrast to random distribution of breakpoints in the FLI1-BCR. No association of breakpoints with various recombination-inducing sequence motifs was identified. The occurrence of small deletions and duplications at the genomic junction is characteristic of involvement of the non-homologous end-joining (NHEJ) repair system, similar to findings at chromosomal breakpoints in pediatric leukemia and lymphoma.
| S-EPMC3575406 | biostudies-literature
Project description:Rhabdomyosarcoma (RMS) is a malignant tumor that represents the most common form of pediatric soft tissue sarcoma. It arises from mesenchymal origin and forms part of the group of small round blue cell tumors of childhood. It has a constant annual incidence of 4.5 cases per 1,000,000 children. The known histological diagnosis of the two major subtypes (embryonal and alveolar) has been recently enhanced by tumor biological markers and molecular differentiation diagnostic tools that have improved not only the updated classification based on risk stratification, but also the treatment approach based on the clinical group. Ewing sarcoma (ES) is a round cell tumor, highly malignant and poorly differentiated that is currently the second most common malignant bone tumor in children. In rare instances, it develops from an extraskeletal origin, classified as extraosseous Ewing sarcoma (EES). We provide an updated, evidence-based and comprehensive review of the molecular diagnosis, clinical and diagnostic approach and a multidisciplinary medical and surgical management according to the latest standard of care for the treatment of pediatric RMS and EES.
| S-EPMC6306718 | biostudies-other
Project description:Ewing sarcoma (EWS) is a highly aggressive cancer with a survival rate of 70%-80% for patients with localized disease and under 30% for those with metastatic disease. Tumor-infiltrating neutrophils (TIN) can generate extracellular net-like DNA structures known as neutrophil extracellular traps (NETs). However, little is known about the presence and prognostic significance of tumor-infiltrating NETs in EWS. Herein, we investigated 46 patients diagnosed with EWS and treated in the Tel Aviv Medical Center between 2010 and 2021. TINs and NETs were identified in diagnostic biopsies of EWS by immunofluorescence. In addition, NETs were investigated in neutrophils isolated from peripheral blood samples of EWS patients at diagnosis and following neoadjuvant chemotherapy. The relationships between the presence of TINs and NETs, pathological and clinical features, and outcomes were analyzed. Our results demonstrate that TIN and NETs at diagnosis were higher in EWS patients with metastatic disease compared with those with local disease. High NET formation at diagnosis predicted poor response to neoadjuvant chemotherapy, relapse, and death from disease (p < 0.05). NET formation in peripheral blood samples at diagnosis was significantly elevated among patients with EWS compared with pediatric controls and decreased significantly following neoadjuvant chemotherapy. In conclusion, NET formation seems to have a role in the EWS immune microenvironment. Their presence can refine risk stratification, predict chemotherapy resistance and survival, and serve as a therapeutic target in patients with EWS.
| S-EPMC10823276 | biostudies-literature
Project description:PURPOSE:Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS. METHODS:We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas. RESULTS:Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively. CONCLUSION:In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.
| S-EPMC7607515 | biostudies-literature
Project description:A 16-year-old male was diagnosed with Ewing sarcoma of the ribcage with pulmonary metastases. Six months after completion of scheduled therapy, he was found to have a new intracardiac mass, presumed recurrent Ewing sarcoma. EWSR1 fusion was not detected by droplet digital polymerase chain reaction from blood plasma. After no improvement with salvage chemotherapy, he underwent surgical resection that identified a low-grade spindle cell sarcoma. Despite the near-synchronous presentation of 2 unrelated sarcomas, extensive genomic analyses did not reveal any unifying somatic or germline mutations nor any apparent cancer predisposition. This case also highlights the potential role of utilizing plasma cell-free DNA for diagnosing tumors in locations where biopsy confers high morbidity.
| S-EPMC5498269 | biostudies-literature
Project description:Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of defects in the midzone, a midline structure located between segregating chromatids during anaphase. Defects in the midzone can lead to the failure of cytokinesis and can result in the induction of aneuploidy. The similarity among the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the inhibition of EWS as the key mechanism for the induction of midzone defects. Supporting this observation, the ectopic expression of EWS rescues the high incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered that EWS interacts with Aurora B kinase, and that EWS is also required for recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in the RGG3 domain of EWS is essential for both Aurora B interaction and the recruitment of Aurora B to the midzone. Here, we propose that the impairment of EWS-dependent midzone formation via the recruitment of Aurora B is a potential mechanism of Ewing sarcoma development.
| S-EPMC4128884 | biostudies-other
Project description:Ewing sarcoma (ES) is thought to arise from mesenchymal stem cells and is the second most common bone sarcoma in pediatric patients and young adults. Given the dismal overall outcomes and very intensive therapies used, there is an urgent need to explore and develop alternative treatment modalities including immunotherapies. In this article, we provide an overview of ES biology, features of ES tumor microenvironment (TME) and review various tumor-associated antigens that can be targeted with immune-based approaches including cancer vaccines, monoclonal antibodies, T cell receptor-transduced T cells, and chimeric antigen receptor T cells. We highlight key reasons for the limited efficacy of various immunotherapeutic approaches for the treatment of ES to date. These factors include absence of human leukocyte antigen class I molecules from the tumor tissue, lack of an ideal surface antigen, and immunosuppressive TME due to the presence of myeloid-derived suppressor cells, F2 fibrocytes, and M2-like macrophages. Lastly, we offer insights into strategies for novel therapeutics development in ES. These strategies include the development of gene-modified T cell receptor T cells against cancer-testis antigen such as XAGE-1, surface target discovery through detailed profiling of ES surface proteome, and combinatorial approaches. In summary, we provide state-of-the-art science in ES tumor immunology and immunotherapy, with rationale and recommendations for future therapeutics development.
| S-EPMC7725096 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE36857: Goldengate Methylation analysis: Ewing Sarcoma GSE36858: 5- AZA treatment of EWS cell lines Refer to individual Series
2012-09-01 | E-GEOD-36859 | biostudies-arrayexpress
Project description:Ewing sarcoma is a malignant pediatric bone and soft tissue tumor. Although the 5-year survival rate of localized disease approaches 75%, the prognosis of metastatic and/or therapy-resistant disease remains dismal despite the wide use of aggressive therapeutic strategies. We previously reported that high expression of glutathione S-transferase M4 (GSTM4) in primary tumors correlates with poor patient outcomes. GSTM4 is required for oncogenic transformation and mediates resistance to chemotherapeutic drugs in Ewing sarcoma cells. Here, we performed RNA-sequencing analyses of Ewing sarcoma cells and combined our results with publicly available datasets to demonstrate that GSTM4 is a major GST specifically expressed in Ewing sarcoma. Pharmacological inhibition of GSTM4 activity using a pan GST inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), significantly limited cellular proliferation and oncogenic transformation of Ewing sarcoma cells. Moreover, combined use of NBDHEX and etoposide synergistically increased cytotoxicity, suggesting a role for GSTM4 as an inhibitor of apoptosis. Mechanistic studies revealed that GSTM4 limits apoptosis owing to its ability to interact with Apoptosis Signal-regulating Kinase 1 (ASK1) and inhibit signaling via the c-Jun N-terminal Kinase axis. To exploit our observation that GSTM4 expression is specifically up-regulated in Ewing sarcoma, we tested the effect of a GSTM4-activated anti-cancer agent, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate or JS-K, on tumor growth and survival. We found that JS-K robustly decreased Ewing sarcoma cell viability and xenograft tumor growth and improved overall survival of xenograft mice. Our data suggest that GSTM4 is a novel therapeutic target for the treatment of high GSTM4-expressing Ewing sarcoma. Strategies that combine standard chemotherapy with agents that inhibit GSTM4, that are activated by GSTM4, or that block GSTM4/ASK1 interactions, can potentially be more specific and/or efficacious than standard therapeutic approaches.
| S-EPMC4123608 | biostudies-other