Gene Summary

Gene:EWSR1; EWS RNA binding protein 1
Aliases: EWS, EWS-FLI1, bK984G1.4
Summary:This gene encodes a multifunctional protein that is involved in various cellular processes, including gene expression, cell signaling, and RNA processing and transport. The protein includes an N-terminal transcriptional activation domain and a C-terminal RNA-binding domain. Chromosomal translocations between this gene and various genes encoding transcription factors result in the production of chimeric proteins that are involved in tumorigenesis. These chimeric proteins usually consist of the N-terminal transcriptional activation domain of this protein fused to the C-terminal DNA-binding domain of the transcription factor protein. Mutations in this gene, specifically a t(11;22)(q24;q12) translocation, are known to cause Ewing sarcoma as well as neuroectodermal and various other tumors. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1 and 14. [provided by RefSeq, Jul 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:RNA-binding protein EWS
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (12)

Cancer Overview

Overview: The EWS (EWSR1) gene is involved in translocations in Ewing's sarcoma, clear cell sarcoma, desmoplastic small round cell tumor and myxoid liposarcoma. The Ewing sarcoma family of tumours is characterised by recurrent translocations that fuse EWS to one of the following genes FLI1 (>90% of cases), ERG, ETV1, E1AF and FEV. In clear cell sarcoma, DSRCT and myxoid liposarcoma EWS is fused to ATF1, WT1 and CHOP respectively.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (20)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Ewing's Sarcomat(11;22)(q24;q12) EWSR1-FLI1 Translocation in Ewing's Sarcoma
The t(11;22)(q24;q12) translocation is present in over 90% of Ewing's sarcoma cases. The resulting EWS-FLI1 fusion gene has been demonstrated to have oncogenic potential. Many alternative forms of the translocation exist, corresponding to variations in the locations of the EWS and FLI1 breakpoints. The most common form, "Type 1", accounts for approximately 60% of cases and consists of the first seven exons of EWS joined to exons 6-9 of FLI1. "Type 2", accounts for approximately 25% of cases and also includes FLI1 exon 5. The type of translocation has been related to prognosis.
View Publications366
Soft Tissue SarcomaEWSR1 and Soft Tissue Sarcoma View Publications356
Bone Cancer (primary)EWSR1 and Bone Cancer View Publications96
Ewing's SarcomaEWSR1-FLI1 Fusion Transcript Structure and Prognosis?Prognostic
There is wide variation in EWS-FLI1 transcripts. 'Type 1' are created as a result of fusion between exons 7 of EWS and 6 of FLI1, and have reported to be associated with an improved outcome compared to other types of EWS-FLI1 fusions (Zoubek, 1996 and de Alava, 1998). However, in a subsequent COG study of 132 patients (van Doorninck, 2010) concluded that current intensive treatment protocols for localized ESFT have erased the clinical disadvantage that was formerly observed in patients with non-type 1 fusions.
View Publications28
Ewing's Sarcoma t(7;22)(p22;q12) EWS-ETV1 Translocation in Ewing's Sarcoma View Publications27
Salivary Gland CancerEWSR1 and Salivary Gland Cancer View Publications29
Desmoplastic Small Round Cell Tumourt(11;22)(p13;q12): EWSR1-WT1 in Desmoplastic Small Round Cell Tumour
DSRCT is a rare and an aggressive malignancy characterised by a translocation of the EWSR1 and WT1 genes, resulting in a EWSR1-WT1 fusion protein.
View Publications28
Ewing's Sarcomat(20;22) EWSR1-NFATC2 in Ewing's Sarcoma
A rare variation of the EWSR1 translocation in Ewing's sarcoma involves the NFATC2 gene on chromosome 20.
View Publications12
Vulvar CancerEWSR1 and Vulvar Cancer View Publications5
Uterine SarcomaEWSR1 and Uterine Cancer View Publications5
Bladder CancerEWSR1 and Bladder Cancer View Publications2
Bone Cancer (primary)t(18;22)(q23;q12) EWSR1-NFATC1 fusion in hemangioma of the bone
Arbajian et al, 2013 reported a novel t(18;22)(q23;q12) in a hemangioma of the bone.
View Publications1
-EWSR1 and Sweat Gland Neoplasms View Publications0
Ewing's Sarcomat(21;22) EWSR1-ERG Translocations in Ewing's Sarcoma
Ewing's Sarcomat(17;22)(q12;q12) EWSR1-E1AF Translocation in Ewing's Sarcoma
Chondrosarcomat(9;22)(q22;q12) in Extraskeletal Myxoid Chondrosarcoma
Skin Cancert(12; 22)(q13; q12) Translocation in Clear Cell Sarcoma
The t(12;22)(q13;q12) is characteristic of malignant melanoma of soft parts (clear cell sarcoma). This fuses the ATF1 gene on chromosome 12 with the EWS gene on chromosome 22.
-EWSR Translocations in Cutaneous Syncytial Myoepithelioma
Jo et al (2013) reported EWSR1 gene rearrangements detected by FISH in 14/17 (82%) cases of Cutaneous Syncytial Myoepithelioma (usually a benign condition). Testing for potential fusion partners (PBX1, ZNF444, POU5F1, DUX4, ATF1, CREB1, NR4A3, DDIT3, and NFATc2) was negative so the authors suggest that this likely involves a novel fusion partner.
Ewing's Sarcomat(2;22) EWSR1-FEV Translocation in Ewing's Sarcoma
Wilms TumourEWSR1 and Wilms Tumour View Publications4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: EWSR1 (cancer-related)

Khwaja R, Mantilla E, Fink K, Pan E
Adult Primary Peripheral PNET/Ewing's Sarcoma of the Cervical and Thoracic Spine.
Anticancer Res. 2019; 39(8):4463-4465 [PubMed] Related Publications
This case report describes a patient with a rare occurrence of primary spinal intramedullary Ewing's sarcoma (ES) in the cervical and thoracic spine. The older age of disease occurrence, uncommon location in the cervical and thoracic spine, and EWSR1 gene fusion as the basis of diagnosis are unique features of this case. There is no clear protocol for treatment of primary extraskeletal ES of the spine, with controversy between evidence for pursuing surgery versus a combination of radiation and chemotherapy. Our patient was treated with temozolomide chemotherapy for recurrent metastatic disease of primary ES of the spine.

Pei J, Zhao X, Patchefsky AS, et al.
Clinical application of RNA sequencing in sarcoma diagnosis: An institutional experience.
Medicine (Baltimore). 2019; 98(25):e16031 [PubMed] Free Access to Full Article Related Publications
Accurate diagnoses of sarcoma are sometimes challenging on conventional histomorphology and immunophenotype. Many specific genetic aberrations including chromosomal translocations have been identified in various sarcomas, which can be detected by fluorescence in situ hybridization and polymerase chain reaction analysis. Next-generation sequencing-based RNA sequencing can screen multiple sarcoma-specific chromosome translocations/fusion genes in 1 test, which is especially useful for sarcoma without obvious differentiation. In this report, we utilized RNA sequencing on formalin-fixed paraffin-embedded (FFPE) specimens to investigate the possibility of diagnosing sarcomas by identifying disease-specific fusion genes. Targeted RNA sequencing was performed on 6 sarcoma cases. The expected genetic alterations (clear cell sarcoma/EWSR1-ATF1, Ewing sarcoma/EWSR1-FLI1, myxoid liposarcoma/DDIT3-FUS) in four cases were detected and confirmed by secondary tests. Interestingly, three SS18 fusion genes (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) were identified in a synovial sarcoma case. A rare fusion gene (EWSR1-PATZ1) was identified in a morphologically challenging case; which enabled us to establish the diagnosis of low grade glioneural tumor. In conclusion, RNA sequencing on FFPE specimen is a reliable method in establishing the diagnosis of sarcoma in daily practice.

Koelsche C, Kriegsmann M, Kommoss FKF, et al.
DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.
J Cancer Res Clin Oncol. 2019; 145(5):1273-1281 [PubMed] Related Publications
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.

Demicco EG
Molecular updates in adipocytic neoplasms
Semin Diagn Pathol. 2019; 36(2):85-94 [PubMed] Related Publications
Adipocytic neoplasms include a diversity of both benign tumors (lipomas) and malignancies (liposarcomas), and each tumor type is characterized by its own unique molecular alterations driving tumorigenesis. Work over the past 30 years has established the diagnostic utility of several of these characteristic molecular alterations (e.g. MDM2 amplification in well- and dedifferentiated liposarcoma, FUS/EWSR1-DDIT3 gene fusions in myxoid liposarcoma, RB1 loss in spindle cell/pleomorphic lipoma). More recent studies have focused on additional molecular alterations which may have therapeutic or prognostic impact. This review will summarize several of the important molecular findings in adipocytic tumors that have been described over the past 10 years.

Wang X, Wang J
Primary sclerosing epithelioid fibrosarcoma of the kidney: Report of two additional cases with a clinicopathological and molecular cytogenetic study.
Exp Mol Pathol. 2019; 107:179-183 [PubMed] Related Publications
We present two cases of sclerosing epithelioid fibrosarcoma (SEF) that arose primarily in the kidney. The tumor in both cases was located at the upper pole of the kidney. Clincially, they were suspected as renal cell carcinomas. However, histological examination revealed densely hyalinized epithelioid tumor suggestive of SEF. The diffuse immunohistochemical staining of MUC4 by neoplastic cells and the presence of EWSR1 gene rearrangement by subsequent florescence in site hybridization (FISH) analysis confirmed the histological diagnosis. Molecular cytogenetic study is highly helpful in arriving at a final diagnosis, in particular to a rare tumor type that arises at an unusual site.

Low SYY, Kuick CH, Seow WY, et al.
Primary paediatric epidural sarcomas: molecular exploration of three cases.
BMC Cancer. 2019; 19(1):182 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary paediatric epidural sarcomas are extremely rare. Overall, there remains a paucity of knowledge in paediatric epidural sarcomas owing to the infrequent number of cases. The Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) is a next-generation sequencing assay that has been reported to be a useful technique to detect recurrent fusion in sarcomas. We report the molecular exploration of 3 primary paediatric epidural sarcomas-one in the cranium (mesenchymal chondrosarcoma) and 2 in the spine (mesenchymal chondrosarcoma and Ewing sarcoma respectively).
CASE PRESENTATION: This is a study approved by the hospital ethics board. Clinico-pathological information from 3 consenting patients with primary epidural sarcomas was collected. These selected tumours are interrogated via Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) for genomic aberrations. Results were validated with RT-PCR and Sanger sequencing. All findings are corroborated and discussed in concordance with current literature. Our findings show 2 variants of the HEY1-NCOA2 gene fusion: HEY1 (exon 4)-NCOA2 (exon 13) and HEY1 (exon 4)-NCOA2 (exon 14), in both mesenchymal chondrosarcoma patients. Next, the Ewing sarcoma tumour is found to have EWSR1 (exon 10)-FLI1 (exon 8) translocation based on NGS. This result is not detected via conventional fluorescence in situ testing.
CONCLUSIONS: This is a molecularly-centered study based on 3 unique primary paediatric epidural sarcomas. Our findings to add to the growing body of literature for these exceptionally rare and malignant neoplasms. The authors advocate global collaborative efforts and in-depth studies for targeted therapy to benefit affected children.

Batsis ID, Offenbacher R, Rybinski B, et al.
Systemic manifestations of extraskeletal myxoid chondrosarcoma associated with a novel t(2;22)(q34;q12) EWS translocation in a child and a review of the literature.
Pediatr Hematol Oncol. 2018 Oct - Nov; 35(7-8):434-441 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma (EMC), a soft-tissue sarcoma with unique clinicopathologic features and characteristic chromosomal translocations, is extremely rare in the pediatric population. We, herein, present the case of a 7-year-old boy with profound microcytic hypochromic anemia, poor weight gain and a mid-thoracic paraspinal mass that was identified as EMC. Systemic manifestations of localized, nonmetastatic EMC have never been described in the pediatric population, yet our patient's anemia and poor weight gain resolved after successful surgical resection of the tumor, suggesting that localized EMC can present with systemic manifestations. The tumor also contained a novel t(2;22)(q34;q12) translocation involving the EWSR1 gene, which is consistent with additional reports suggesting that a growing list of translocations can drive formation of, and potential new management strategies for, EMC.

Kojima Y, Tanabe M, Kato I, et al.
Myoepithelioma-like tumor of the vulvar region showing infiltrative growth and harboring only a few estrogen receptor-positive cells: A case report.
Pathol Int. 2019; 69(3):172-176 [PubMed] Related Publications
Recently, a new entity "myoepithelioma-like tumor of the vulvar region (MELTVR)" was proposed as a rare mesenchymal neoplasm arising in vulvar regions of adult women. While MELTVRs morphologically resemble soft tissue myoepitheliomas and extraskeletal myxoid chondrosarcomas, they have a unique immunohistochemical profile (positive for epithelial membrane antigen and estrogen receptor, negative for S100 protein and glial fibrillary acidic protein, and loss of INI1/SMARCB1 expression), and lack EWSR1 and NR4A3 gene rearrangement, as seen by fluorescence in situ hybridization. MELTVRs are usually well-demarcated tumors, with no reports of extensive infiltrative growth. In the current report, we present an unusual case of MELTVR showing infiltrative growth and harboring only a few estrogen receptor-positive cells, which might indicate a variation in this rare tumor.

Thway K, Fisher C
Mesenchymal Tumors with EWSR1 Gene Rearrangements.
Surg Pathol Clin. 2019; 12(1):165-190 [PubMed] Related Publications
Among the various genes that can be rearranged in soft tissue neoplasms associated with nonrandom chromosomal translocations, EWSR1 is the most frequent one to partner with other genes to generate recurrent fusion genes. This leads to a spectrum of clinically and pathologically diverse mesenchymal and nonmesenchymal neoplasms, variably manifesting as small round cell, spindle cell, clear cell or adipocytic tumors, or tumors with distinctive myxoid stroma. This review summarizes the growing list of mesenchymal neoplasms that are associated with EWSR1 gene rearrangements.

Aghajan Y, Malicki DM, Levy ML, Crawford JR
Atypical central neurocytoma with novel EWSR1-ATF1 fusion and MUTYH mutation detected by next-generation sequencing.
BMJ Case Rep. 2019; 12(1) [PubMed] Related Publications
We present the case of a 13-year-old boy with a very unusual periventricular atypical central neurocytoma with unique molecular features treated with subtotal surgical resection and photon intensity-modulated radiotherapy. Histological features were most consistent with atypical central neurocytoma. However, next-generation sequencing analysis revealed a novel EWSR1-ATF1 gene fusion (EWSR1-ATF1) as well as a MUTYH mutation. The EWSR1-ATF1 raised the possibility of Ewing sarcoma or angiomatoid fibrous histiocytoma, however, FLI-1 immunohistochemistry was negative. MUTYH mutations have been reported in diffuse midline paediatric glioma. The role of EWSR1-ATF1 and MUTYH mutations in central nervous system tumours is not well established. We present the first case of EWSR1-ATF1 and MUTYH mutation in a rare paediatric atypical central neurocytoma. Further studies are indicated to elucidate the consequences of these gene alterations in the context of paediatric central nervous system tumours as well as to investigate the potential role for targeted therapies.

Yun S, Kim SH, Cho HS, et al.
EWSR1-PBX3 fused myoepithelioma arising in metatarsal bone: Case report and review of the literature.
Pathol Int. 2019; 69(1):42-47 [PubMed] Related Publications
Intraosseous myoepithelial tumors are very rare. Due to the low incidence and diverse histologic features, accurate diagnosis is challenging, necessitating ancillary immunohistochemistry. Moreover, genetic abnormality in this tumor was not revealed until recently. Although EWSR1 translocation is involved in half of the cases of intraosseous myoepithelioma, only a few cases have indicated its counterpart gene. We herein describe a case of intraosseous myoepithelioma with a novel localization in the fourth metatarsal bone of a 36-year-old female. Cytogenetic analysis using next generation sequencing detected a rare EWSR1-PBX3 fusion. Next generation sequencing could be useful in understanding the cytogenetic characteristics of intraosseous myoepithelioma, and in obtaining an accurate diagnosis of this rare condition.

Parcesepe P, Giordano G, Zanella C, et al.
Colonic Ewing Sarcoma/PNET associated with liver metastases: A systematic review and case report.
Pathol Res Pract. 2019; 215(2):387-391 [PubMed] Related Publications
Ewing Sarcoma is a highly lethal undifferentiated tumor of bone. ES is a small round cell tumor with etiological and characteristic chromosomal translocations between TET/FET (TLS/FUS, EWSR1, and TAF15) and ETS (E26 transformation-specific) family genes. Generally, therapeutic approach for metastatic Ewing Sarcoma includes both local (surgery and radiotherapy) and systemic (chemotherapy) disease control with an overall cure rate of 20%. For extra-osseous tumors, the most common primary sites of disease are trunk, extremities, head and neck, retroperitoneum. Among other sites, Ewing Sarcoma/PNET may also rarely arise in colon and rectum. Even if colonic Ewing Sarcoma/PNET have been previously reported in 5 cases, none of those reports came from right side of the colon. In this article, we report the first case of right-sided Ewing Sarcoma with synchronous liver metastases completely responding to first line chemotherapy. Furthermore, we provide a systematic qualitative review of the current literature on adult colorectal Ewing Sarcoma using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Fukuda H, Kato I, Furuya M, et al.
A novel partner of TFE3 in the Xp11 translocation renal cell carcinoma: clinicopathological analyses and detection of EWSR1-TFE3 fusion.
Virchows Arch. 2019; 474(3):389-393 [PubMed] Related Publications
The renal cell carcinomas associated with Xp11 translocations (Xp11 translocation RCCs) harbor gene fusions involving TFE3, a member of the microphthalmia-associated transcription factor (MiTF) family. In the present study, we identified a novel partner of TFE3, Ewing sarcoma breakpoint region 1 (EWSR1), in an Xp11 translocation RCC. A 57-year-old Japanese woman without special disease history was referred to us for treatment of an RCC. The resected tumor displayed an alveolar growth pattern with high-grade nuclei. The tumor was diffusely positive for TFE3 and cathepsin K. Anchored multiplex PCR revealed a novel fusion, EWSR1-TFE3. Fluorescent in situ hybridization analysis demonstrated the rearrangements of EWSR1 and TFE3. RT-PCR analysis confirmed the chimeric transcript. No neoplasm with EWSR1-TFE3 has been reported so far, in any organ. The results will expand the genomic spectrums of Xp11 translocation RCCs and contribute to better understanding of the roles of the MiTF family in the oncogenic process.

Lin L, Huang M, Shi X, et al.
Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1.
Nucleic Acids Res. 2019; 47(3):1255-1267 [PubMed] Free Access to Full Article Related Publications
As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer-associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.

Devecchi A, De Cecco L, Dugo M, et al.
The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial-mesenchymal transition, and immune response.
Cancer Commun (Lond). 2018; 38(1):70 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1 (EWSR1)-Wilm's tumor suppressor (WT1) translocation. We used whole-exome sequencing to interrogate six consecutive pre-treated DSRCTs whose gene expression was previously investigated.
METHODS: DNA libraries were prepared from formalin-fixed, paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500. Raw sequence data were aligned to the reference genome with Burrows-Wheeler Aligner algorithm. Somatic mutations and copy number alterations (CNAs) were identified using MuTect2 and EXCAVATOR2, respectively. Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis (IPA) software.
RESULTS: A total of 137 unique somatic mutations were identified: 133 mutated genes were case-specific, and 2 were mutated in two cases but in different positions. Among the 135 mutated genes, 27% were related to two biological categories: DNA damage-response (DDR) network that was also identified through IPA and mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) already demonstrated to be relevant in DSRCT. The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre-mRNA. Half of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins, which were recently recognized as a new class of DDR players. CNAs in genes/gene families, involved in MErT/EMT and DDR, were recurrent across patients and mostly segregated in the MErT/EMT category. In addition, recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were recorded.
CONCLUSIONS: The emerging picture is an extreme inter-tumor heterogeneity, characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.

Roberto GM, Vieira GM, Delsin LEA, et al.
MiR-708-5p is inversely associated with EWS/FLI1 Ewing sarcoma but does not represent a prognostic predictor.
Cancer Genet. 2019; 230:21-27 [PubMed] Related Publications
BACKGROUND: Overall survival of Ewing sarcoma (EWS) remains poor and less than 30% of patients with metastatic or recurrent disease survive despite current treatments. Thus, there is a constant search for new biomarkers for diagnosis, prognosis and prediction of therapy. Numerous studies have reported the abnormal expression of miR-708-5p in tumors of different origins. However, its role in EWS remains unclear.
PROCEDURE: qRT-PCR was performed in nineteen consecutive EWS samples and twelve non-tumor bone samples from age-matched controls. Functional assays were performed in SK-ES-1 cells transfected with miR-708 lentiviral-based vectors and results analyzed in terms of clonogenicity, migration, invasion and western blot.
RESULTS: We show that miR-708-5p is downregulated in EWS tissues though no associations with any prognostic features such as HUVOS grade, event or survival were found in our cohort. Nonetheless, expression levels of this micro-RNA were inversely associated with the presence of the EWS/FLI1 translocation. When miR-708-5p was transfected into the SK-ES-1 cell line, it did not affect migration or clonogenicity, but promoted a significant increase on the invasive potential of cells endorsed with high expression of MMP2.
CONCLUSIONS: Taken together, our results suggest that despite downregulated in EWS samples, this miRNA might represent a secondary genetic alteration derived from the pleiotropic cellular effects of the abnormal EWS/FLI1 transcription factor that does not affect tumor growth but instead, is related with the promotion of tumor invasion, not being suitable for future therapeutic intervention.

Santos F, Martins C, Lemos MM
Fine-needle aspiration features of extraskeletal myxoid chondrosarcoma: A study of cytological and molecular features.
Diagn Cytopathol. 2018; 46(11):950-957 [PubMed] Related Publications
BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a tumor of uncertain differentiation. Few data are available regarding its cytomorphological features in fine-needle aspiration (FNA). Specific cytogenetic alterations involving the NR4A3 gene are found in EMC and can be identified in FNA samples.
METHODS: We retrospectively reviewed 14 FNAs performed in 11 patients with an EMC; 10 FNAs were performed preoperatively on primary tumors; 2 were performed on recurrences and 2 were performed on metastasis. Cytological features were compared with histological findings. Immunohistochemistry (IHC) and molecular studies were performed both in FNA and histological specimens.
RESULTS: A preoperative cytological diagnosis of EMC was rendered in eight FNAs performed in newly diagnosed tumors and in recurrent/metastatic cases. A descriptive diagnosis of a myxoid neoplasm was made in the remaining two cases. Smears were moderately hypercellular, composed of plasmocytoid to fusiform cells, with scant, pale cytoplasm, bland nuclei and inconspicuous nucleoli, dispersed as cords, strands and occasionally with a lace-like pattern, in an abundant chondromyxoid matrix. IHC performed showed focal positivity for S100 and NSE. Fluorescence in situ hybridization technique performed in three FNA specimens showed EWSR1 gene rearrangements in all, concomitant with NR4A3 gene rearrangement in one case. Histological specimens showed typical features of EMC and NR4A3 gene rearrangements were found in all cases tested.
CONCLUSION: FNA cytology is a reliable method to perform a preoperative diagnosis of EMC regarding its cytomorphological and molecular features. Main differential diagnoses include myoepithelial tumors of soft tissue, myxoid liposarcoma and myxofibrosarcoma. Ancillary studies are helpful when coupled with cytomorphology evaluation.

Tang S, Dodd LG
CIC-DUX4 sarcoma diagnosed by fine-needle aspiration cytology: A case report.
Diagn Cytopathol. 2018; 46(11):958-963 [PubMed] Related Publications
The CIC-DUX4 sarcoma is a small round blue cell sarcoma which presents like extraskeletal Ewing sarcoma, but is negative for the EWSR1 gene translocation. The recognition of CIC-DUX4 sarcomas as an aggressive sarcoma may be challenging in fine needle aspirates or small needle core biopsies. We present a case of a 13-year-old female with a fine needle aspiration (FNA) and core needle biopsy (CNB) of a thigh mass showing CIC-DUX4 sarcoma. Cytologic findings include tumor cells with high nuclear to cytoplasmic (N:C) ratio, eccentric nuclei and small nucleoli. The tumor cells were arranged in sheets and singly dispersed with background necrosis. Mitotic figures and apoptosis were present. These findings are similar to cases previously reported. Other reported findings of spindled nuclei, clear cell change and lobular growth pattern were not seen in our case. Immunohistochemical stains showed tumor cells positive for CD99, WT1, vimentin and negative for pancytokeratin, desmin and myogenin, which is the pattern similar to cases previously reported. However, our case was also positive for BCL-2. Fluorescence in situ hybridization (FISH) was negative for EWSR1 and SS18 (SYT) rearrangements and positive for CIC gene rearrangement. On balance, if the following features are seen: (1) a small round blue cell tumor with histomorphology more atypical than that of Ewing sarcoma, (2) cytoplasmic CD99 staining, nuclear WT1 positivity, negative keratin, desmin and myogenin; and (3) EWSR1 rearrangement negative by FISH, then molecular testing for CIC-DUX4 sarcoma should be considered.

Oyama R, Kito F, Qiao Z, et al.
Establishment of a novel patient-derived Ewing's sarcoma cell line, NCC-ES1-C1.
In Vitro Cell Dev Biol Anim. 2018; 54(10):770-778 [PubMed] Related Publications
Ewing's sarcoma is an aggressive mesenchymal tumor characterized by the presence of a unique EWSR1-FLI1 translocation. Ewing's sarcoma primarily occurs in the bone and soft tissues. Cell lines enable researchers to investigate the molecular backgrounds of disease and the significance of genetic alterations in relevant cellular contexts. Here, we report the establishment and characterization of a novel Ewing's sarcoma cell line following primary Ewing's sarcoma tumor tissue culture. The established cell line was authenticated by DNA microsatellite short tandem repeat analysis, characterized by in vitro assays, and named NCC-ES1-C1. The NCC-ES1-C1 cell line grew well for 15 mo and was subcultured more than 50 times during this period. Characterization of the cells revealed that they were not adherent and showed floating features. In conclusion, we successfully established a novel Ewing's sarcoma cell line, NCC-ES1-C1, from primary tumor tissue. The cell line has the characteristic EWSR1-FLI1 gene fusion and exhibits aggressive growth in vitro. Thus, the NCC-ES1-C1 cell line will be a useful tool for investigating the mechanisms of disease and the biological role of the EWSR1-FLI1 fusion gene.

Louati S, Senhaji N, Chbani L, Bennis S
Dis Markers. 2018; 2018:7971019 [PubMed] Free Access to Full Article Related Publications
Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET sarcomas or EPS) are a group of round cell tumors. Malignant round cell tumors form a large and diverse group that includes rhabdomyosarcoma, synovial sarcoma, non-Hodgkin's lymphoma, neuroblastoma, hepatoblastoma, Wilm's tumor, desmoplastic small round cell tumor, and other morphologically similar entities. Differential diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET sarcomas or EPS) is difficult. In addition to morphology and immunohistochemistry (IHC), differential diagnosis of these tumors is based on molecular analysis of the

Bremmer F, Fichtner A, Triefenbach R, et al.
CIC fusion-positive sarcoma of the spermatic cord.
Virchows Arch. 2019; 474(2):253-257 [PubMed] Related Publications
In addition to germ cell tumors and tumors of the sex cord stroma, the WHO classification of testis and paratesticular tumors also contains malignant soft tissue tumors. Among them, liposarcomas of the spermatic cord are the most common entities. Other mesenchymal tumors with smooth muscle, skeletal muscle, fibroblastic/myofibroblastic, or nerve sheath differentiation are rare. Ewing sarcoma is composed of uniform small round cells and typically characterized by translocations of the EWSR1 gene. In rare cases, Ewing sarcoma-like tumors lack an EWSR1 gene fusion. Some of these tumors harbor a specific CIC translocation. However, Ewing-like sarcoma has up to now never been described in the testis or spermatic cord. The present case describes the first EWSR1-negative, undifferentiated round cell sarcoma with CIC translocation of the spermatic cord. Potential differential diagnoses are discussed.

Mok Y, Agaimy A, Wang S, et al.
High-grade myoepithelial carcinoma can show histologically undifferentiated/anaplastic features.
Ann Diagn Pathol. 2018; 37:20-24 [PubMed] Related Publications
High grade malignant tumors with a poorly-/un-differentiated morphology pose significant diagnostic challenges. Increasingly, the use of adjunct immunohistochemical and molecular tests to characterize and delineate the histopathologic phenotype of these tumors has become necessary, particularly in head and neck tumors. Recently, several entities with a poorly-/un-differentiated light microscopic morphology have been defined based on specific immunohistochemical and genetic characteristics. We herein describe two cases of high-grade myoepithelial carcinoma, one occurring in the submandibular gland and the other occurring in the left nasal cavity, both showing undifferentiated histological and anaplastic cytomorphological features. This led to very broad differential diagnostic considerations and the diagnosis was only established after extensive immunohistochemical studies. Molecular testing for HPV was negative in both cases. Gene fusion analysis using a targeted sequencing assay (Archer® FusionPlex® system) did not identify fusions involving PLAG1, HMGA2, EWSR1 or ALK genes in either case. The submandibular tumor showed an aggressive clinical course, with diffuse pulmonary metastases at presentation, whilst the nasal cavity tumor showed only localized disease. Awareness of a subcategory of high-grade myoepithelial carcinomas with undifferentiated light microscopical features is of significant importance in antibody selection for immunohistochemical investigation of poorly-/undifferentiated malignant tumors in the head and neck region. This histological variant of myoepithelial carcinoma adds to the growing list of differential diagnoses in this diagnostically complex and multifaceted field.

Segawa K, Sugita S, Aoyama T, et al.
Detection of specific gene rearrangements by fluorescence in situ hybridization in 16 cases of clear cell sarcoma of soft tissue and 6 cases of clear cell sarcoma-like gastrointestinal tumor.
Diagn Pathol. 2018; 13(1):73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Clear cell sarcoma of soft tissue (CCSST) and clear cell sarcoma-like gastrointestinal tumor (CCSLGT) are malignant mesenchymal tumors that share some pathological features, but they also have several different characteristics. They are well known to express chimeric fusions of Ewing sarcoma breakpoint region 1 (EWSR1) and cAMP response element-binding protein (CREB) family members; namely, EWSR1-activating transcription factor 1 (ATF1) and EWSR1-CREB1. In addition, recent studies have suggested the presence of other fusions.
METHODS: We used fluorescence in situ hybridization to detect specific rearrangements including EWSR1, ATF1, CREB1, and cAMP response element modulator (CREM) in 16 CCSST and 6 CCSLGT cases. We also used reverse transcription polymerase chain reaction (RT-PCR) to detect specific chimeric fusions of EWSR1-ATF1 and EWSR1-CREB1 using fresh tumor samples in available cases.
RESULTS: A total of 15 of 16 CCSST cases (93.8%) had EWSR1 rearrangement, of which 11 (68.8%) also had ATF1 rearrangement, suggestive of the presence of EWSR1-ATF1 fusions. One CCSST case (6.3%) was found to have EWSR1 and CREM rearrangements, and 4 of 6 CCSLGT cases (66.7%) had EWSR1 rearrangement, of which 2 (33.3%) showed ATF1 rearrangement and the other 2 cases (33.3%) showed CREB1 rearrangement. These cases most likely had EWSR1-ATF1 and EWSR1-CREB1 fusions, respectively. RT-PCR was performed in 8 available cases, including 6 CCSSTs and 2 CCSLGTs. All CCSSTs showed EWSR1-ATF1 fusions. Among the 2 CCSLGT cases, one had EWSR1-ATF1 fusion and the other had EWSR1-CREB1 fusion.
CONCLUSIONS: Rearrangements of EWSR1 and ATF1 or EWSR1-ATF1 fusion were predominantly found in CCSST, whereas those of EWSR1 and CREB1 or EWSR1-CREB1 tended to be detected in CCSLGT. A novel CREM fusion was also detected in a few cases of CCSST and CCSLGT. The cases in which EWSR1 rearrangement was detected without definitive partner genes should be considered for the presence of CREM rearrangement.

Hakozaki M, Tamura H, Dobashi Y, et al.
Establishment and Characterization of a Novel Human Clear-cell Sarcoma of Soft-tissue Cell Line, RSAR001, Derived from Pleural Effusion of a Patient with Pleural Dissemination.
Anticancer Res. 2018; 38(9):5035-5042 [PubMed] Related Publications
BACKGROUND/AIM: Clear cell sarcoma (CCS) of soft tissue is exceedingly rare and frequently exhibits aggressive behavior. Toward the goals of improving the aggressive course and poor prognosis of CCS, and establish new therapeutic methods, molecular genetic and biological characterizations of CCS are required.
MATERIALS AND METHODS: A new human CCS cell line (designated RSAR001) was established from the pleural effusion of a 44-year-old man with multiple lung metastases and pleural dissemination. The cell line and its xenograft were characterized including their morphology, immunohistochemistry, cytogenetic analysis, reverse transcription-polymerase chain reaction, direct sequencing analysis, and fluorescence in situ hybridization analysis.
RESULTS: The cell line has been maintained for over 12 months with more than 50 passages. RSAR001 cells exhibited a fascicular or diffuse growth pattern of short spindle- or oval-shaped cells with clear cytoplasm in heterotransplanted tumor, that was similar to the primary tumor. Immunophenotypically, RSAR001 cells in vitro and in vivo exhibited almost the same characteristics as the primary tumor. Cytogenetic analyses revealed a translocation, t(12;22)(q13;q12). Reverse transcription-polymerase chain reaction and direct sequencing analysis detected transcripts of the Ewing sarcoma breakpoint region 1-activating transcription factor 1 (EWSR1-ATF1) type 1 fusion gene. Fluorescence in situ hybridization using a break-apart probe for the EWSR1 gene on 22q12 showed a rearrangement.
CONCLUSION: These findings indicate that the RSAR001 cell line harbors EWSR1-ATF1 type 1 chimeric fusion gene, which is specific to CCS. RSAR001 cells might be useful for investigating biological behaviors and developing new treatments such as molecular-targeting antitumor drugs or immunological drugs for CCS.

Anderson ND, de Borja R, Young MD, et al.
Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.
Science. 2018; 361(6405) [PubMed] Free Access to Full Article Related Publications
Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between

Georgakopoulos N, Diamantopoulos P, Micci F, et al.
An Adult Patient with Early Pre-B Acute Lymphoblastic Leukemia with t(12;17)(p13;q21)/ZNF384-TAF15.
In Vivo. 2018 Sep-Oct; 32(5):1241-1245 [PubMed] Free Access to Full Article Related Publications
This is a case report of a 46-year-old man diagnosed with early pre-B acute lymphoblastic leukemia (ALL), bearing the translocation t(12;17)(p13;q21) as the sole chromosomal abnormality. This is a rare chromosomal abnormality that has been reported in approximately 25 cases worldwide. FISH analysis revealed a rearrangement of ZNF384 (12p13) and TAF15 (17q12) genes, which is usually associated with a pre-B ALL phenotype with co-expression of the myeloid markers CD13 and/or CD33. ZNF384 encodes a zinc finger protein, which acts as a transcription factor, regulating the expression of several matrix metalloproteinases and TAF15 belongs to the FET (FUS, EWS, and TAF15) family, consisting of RNA and DNA-binding proteins. Unlike most of the cases where CD10 expression was absent or weak, in our case CD10 was highly expressed. The prognostic significance of ZNF384/TAF15 fusion is not very clear since several reports support a generally good prognosis, while others support a poor clinical outcome. Our patient was treated with the German multicenter ALL (GMALL) protocol for B-ALL, but experienced a fulminant gram-negative sepsis and eventually died during induction therapy.

Lu Q, Lu M, Li D, Zhang S
MicroRNA‑34b promotes proliferation, migration and invasion of Ewing's sarcoma cells by downregulating Notch1.
Mol Med Rep. 2018; 18(4):3577-3588 [PubMed] Free Access to Full Article Related Publications
Ewing's sarcoma is the second most frequent bone and soft tissue sarcoma, which is commonly driven by the Ewing's sarcoma breakpoint region 1‑friend leukemia integration 1 transcription factor (EWS‑FLI1) fusion gene. Since microRNAs (miRs) can act as either oncogenes or tumor suppressor genes in human cancer, and miR‑34b has been reported to act as a tumor suppressor, the role of miR‑34b in Ewing's sarcoma was investigated in the present study. The results demonstrated that miR‑34b expression levels were higher in tumor samples compared within normal tissue samples. Notably, miR‑34b expression levels were significantly higher in EWS‑FLI1‑positive samples compared within EWS‑FLI1‑negative samples. The effects of miR‑34b expression on cell proliferation, migration and invasion were also examined. miR‑34b expression was inhibited using small interfering (si)RNA targeting the fusion gene. Transfection of a miR‑34b precursor sequence into siRNA‑treated tumor cells resulted in a significant increase in cell growth, migration and invasion compared within the control group. In addition, the adhesive ability was increased in the Ewing's sarcoma cell line RD‑ES, but not A673, following miR‑34b upregulation. Conversely, downregulation of miR‑34b expression led to a significant decrease in cell growth, migration and invasion. Notch has previously been reported to serve either oncogenic or tumor suppressive roles in human cancer. The results indicated that Notch1 and its target genes, Hes family BHLH transcription factor 1 and Hes‑related family BHLH transcription factor with YRPW motif 1, were suppressed by miR‑34b directly In conclusion, EWS‑FLI1 may modulate miR‑34b expression directly or indirectly, and miR‑34b potentially has an oncogenic role in Ewing's sarcoma by downregulating Notch1.

Lui GYL, Grandori C, Kemp CJ
CDK12: an emerging therapeutic target for cancer.
J Clin Pathol. 2018; 71(11):957-962 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3' end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.

Machiela MJ, Grünewald TGP, Surdez D, et al.
Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.
Nat Commun. 2018; 9(1):3184 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

Kaeding KE, Zaret KS
Microsatellite enhancers can be targeted to impair tumorigenesis.
Genes Dev. 2018; 32(15-16):991-992 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Dysregulation of repetitive elements has been implicated in many cancers and other human diseases; however, the role of repetitive elements remains largely unexplored. In this issue of

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