EWSR1 (Ewing sarcoma breakpoint region 1)

2010-08-01   Jean-Loup Huret  

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Identity

HGNC
EWSR1
LOCATION
22q12.2
IMAGE
Atlas Image
LEGEND
t(21;22)(q22;q12) R-banding - Courtesy Francine Mugneret
IMAGE
Atlas Image
LEGEND
t(11;22)(q24;q12) FISH with a double color EWSR1 probe - Courtesy Francine Mugneret
LOCUSID
2130
ALIAS
EWS,EWS-FLI1,bK984G1.4
FUSION GENES
Show Gene Fusions

DNA/RNA

Atlas Image

Description

Spans 32.5 kb, in a centromere to telomere direction on plus strand; transcript of 2654 bp from 17 exons for the canonical form, with a coding sequence of 1971 nt.

Transcription

According to Ensembl, there are 25 transcripts, of which 16 different transcripts code for proteins.

Proteins

Atlas Image

Description

656 amino acids for the canonical form identified in 1993 (Plougastel et al., 1993), 68.5 kDa. From N-term to C-term: a transactivation domain (TAD) containing multiple degenerate hexapeptide repeats (consensus SYGQQS) (glycine, glutamine, serine, tyrosine rich or SYGQ rich, where the tyrosine is mandatory): amino acids 1 to 285, with a site interacting with SF1 from aa 228 to 264 and an IQ domain, which binds calmodulin (aa 256-285), 3 arginine/glycine rich domains (RGG regions) (aa 300-340, 454-513 (arginine/glycine/proline rich), and aa 559-640), a RNA recognition motif (RRM or RNA-binding domain (RBD): aa 361-447), and a RanBP2 type Zinc finger (aa 518-549).
Atlas Image
Uniform small round cells with fine chromatin and pale eosinophilic cytoplasm (left); transmembrane glycoprotein MIC2/CD99 (right) - Courtesy Francine Mugneret

Expression

EWSR1 is ubiquitely expressed (Alliegro and Alliegro, 1996; Andersson et al., 2008). In particular, EWSR1 is required for cell survival in the central nervous system (Azuma et al., 2007).

Localisation

Mainly in the nucleus. It has also been found in the cytoplasm, and associated with the plasma membrane. Expression of EWSR1 in the various subcellular compartments is affected by the methylation state of its RNA-binding domain (Belyanskaya et al., 2003).
EWSR1 is mainly found in the nucleus, and more rarely in the cytoplasm than its two homologs FUS and TAF15; the 3 proteins participate in nucleo-cytoplasmic shutlling; EWSR1 localized poorly in stress granules when cells were exposed to environmental stress (stress granules are cytoplasmic particles composed of translation pre-initiation complexes, mRNAs and RNA-binding proteins) (Andersson et al., 2008), in Cajal bodies, and nucloli. Localization of EWSR1 in different subcellular compartments reflects a dynamic distribution during cell cycle: predominant nuclear localization in interphase cells, perichromosomal localization in prometaphase cells, and cytoplasmic localization in metaphase cells, association with microtubules in quiescent cells (Leemann-Zakaryan et al., 2009).

Function

RNA binding protein, single strand DNA binding.
Role in transcriptional regulation for specific genes and in mRNA splicing: Transcription and pre-mRNA slicing, a post-transcriptional activity, are closely related.
EWSR1 plays a role in transcription initiation: EWSR1 is able to associate with the basal transcription factor TFIID (a multiprotein complex composed of the TATA-binding protein (TBP) and TBP-associated factors (TAFIIs)) and the RNA polymerase II complex. EWSR1 acts as a transcriptional activator (Bertolotti et al., 1998). It associates with heterogeneous RNA-binding proteins (hnRNPs), such as RBM38 and RBM39 (RNA binding motif proteins 38 and 39, 20q13 and 20q11 respectively) (Zinszner et al., 1994).
EWSR1 associates with EP300 and CREBBP. EWSR1 functions as a co-activator of CREBBP-dependent transcription factors. EWSR1-EP300/CREBBP mediates FOS activation, as well as HNF4 genes activation (Rossow and Janknecht, 2001; Araya et al., 2003). CREBBP is a transcription co-activator which enables the interaction between various transcription factors and RNA Pol II, brings enzymes to the promoter, and remodels the chromatin favouring the open status (Gervasini, 2009).
EWSR1 also activates other transcription factors such as POU4F1 (or BRN3A, 13q13) (Gascoyne et al., 2004), POU5F1 (or OCT4, 6p21) (Lee et al., 2005).
SF1 (splicing factor 1, 11q13, also called ZFM1) represses the transactivation domain of EWSR1; SF1, a transcription activator or repressor involved with many pathways, may negatively modulate transcription of target genes coordinated by EWSR1 (Zhang et al., 1998).
EWS functions as a docking molecule by recruiting serine-arginine (SR) splicing factors such as SRSF10 (serine/arginine-rich splicing factor 10, 1p36, or TASR, which represses pre-mRNA splicing) to RNA Pol II, coupling gene transcription to RNA splicing by binding to hyperphosphorylated RNA Pol II through its N-term part domain, and SR splicing factors through its C-term domain (Yang et al., 2000).
YBX1 (Y box binding protein 1, 1p34), a multifunctional protein that shuttles between the cytoplasm (where it binds to mRNA and regulates mRNA translation) and the nucleus (where it regulates transcription of diverse target genes), interacts with the C-term domain of EWS. This interaction docks YBX1 to RNA Pol II to participate in pre-mRNA splicing (Chansky et al., 2001).
SMN1 (survival of motor neuron 1, telomeric, 5q13) plays a major role in the pre-mRNA splicing machinery (role in spliceosomal snRNP assembly in the cytoplasm and in pre-mRNA splicing in the nucleus) (Pellizzoni et al., 1998). SMN1, through its Tudor region, binds the RG1 region of EWSR1 (Young et al., 2003).
RNU1-2 (RNA, U1 small nuclear 2, 1p36, also called U1C), another splicing protein, also interacts with EWSR1 (Knoop and Baker, 2000).
EWSR1 is phosphorylated by PRKC (protein kinase C) though its IQ domain, which inhibits RNA binding of EWSR1; CALM (calmodulin) binding to EWSR1 inhibits PRKC phosphorylation (Deloulme et al., 1997).
EWSR1 interacts with POU4F2 (4q31), a gene which regulates differentiation of neuronal cells (Gascoyne et al., 2004). EWSR1 interacts with LMNA (lamin A/C, 1q22, a component of the nuclear envelope which interacts with DNA, histones and transcriptional repressors) is essential for pre-B lymphocyte development and, during meiosis, in XY pairing and in meiotic recombination, as cross-overs are reduced in ews-/- spermatocytes. Loss of EWSR1 results in premature cellular senescence (Li et al., 2007). EWSR1 is required for proper localization of aurora B during mitosis, and maintains mitotic spindle integrity (Azuma et al., 2007).
It also interacts with BARD1 (BRCA1 associated RING domain 1) (Spahn et al., 2002).
EWSR1 and CCNL1 (cyclin L1, 3q25), are interacting partners of TFIP11 (tuftelin-interacting protein 11, 22q12), a protein functionally related to the spliceosome and involved in pre-mRNA splicing) (Tannukit et al., 2008).

Homology

Member of the TET family of RNA binding proteins, with FUS (TLS) and TAF15 (TAFII68). TET is for Tls, Ewsr1, TafII68). TET proteins contain specific structural domains not found elsewhere in other RNA binding proteins, i.e. a N-term SYGQ rich (TAD: transactivation domain), a conserved RNA-binding domain (RRM: RNA recognition motif), RG rich regions, and a Cys2-Cys2 Zinc finger which can bind nucleic acids; they are also functionally related (reviews in Law et al., 2006; Tan and Manley, 2009).

Implicated in

Entity name
Various tumours (see details below)
Atlas Image
Entity name
Ewings sarcoma/Peripheral neurectodermal tumour (ES/PNET)
Note
- With: t(11;22)(q24;q12) --> FLI1 - EWSR1 (Delattre et al., 1992; Bailly et al., 1994; Thomas et al., 1994; records in the Mitelman Database).
- With: t(2;22)(q36;q12) --> FEV - EWSR1 (Llombart-Bosch et al., 2000; Peter et al., 2001; Navarro et al., 2002; Hattinger et al., 1999; Wang et al., 2007).
- With: t(7;22)(p22;q12) --> ETV1 - EWSR1 (Jeon et al., 1995; Peter et al., 2001; Zielenska et al., 2001; Wang et al., 2007).
- With: t(17;22)(q21;q12) --> ETV4 - EWSR1 (Kaneko et al., 1996; Urano et al., 1996; Urano et al., 1998).
- With: inv(22)(q12q12) --> PATZ1 - EWSR1 (Mastrangelo et al., 2000)
- With: t(21;22)(q21;q12) --> ERG - EWSR1 (Dunn et al., 1994; Giovannini et al., 1994; Kaneko et al., 1997; Maire et al., 2008; Minoletti et al., 1998; Sorensen et al., 1994; Zoubek et al., 1994; Zucman et al., 1993b; Shing et al., 2003; Peter et al., 1996).
Note: Rare cases of ES/PNET have been described without EWSR1 involvement, but, instead:
- with: t(2;16)(q35;p11) --> FUS - FEV (Navarro et al., 2002) or,
- with: t(16;21)(p11;q22) --> FUS - ERG (Shing et al., 2003; Berg et al., 2009). To be noted that the same t(16;21)(p11;q22) has been found in rare cases of acute myeloid leukaemia.
A t(11;22)(q24;q12) has also been found in a case of cerebellar PNET (Jay et al., 1996).
Disease
Ewings sarcoma/Peripheral neurectodermal tumour spectrum is a group of sarcomas with small blue round cells with more (PNET side) or less (Ewing side) features of neuroectodermal differentiation. ES/PNET entity also includes peripheral neuroepithelioma and Askin tumour. These tumours display both mesenchymal stem cell and neural crest stem cell properties. It is mainly found in adolescents and young adults. Cytogenetics and immunochemistry are essential for the differential diagnosis with other sarcomas (review in Romeo and Dei Tos, 2010).
Prognosis
Prognosis has dramatically improved, from less than 10% of long survivors, to a 5-year disease free survival of 75% for patients with a localized disease, and 25-30% for those with a metastatic disease (Ludwig, 2008).
Cytogenetics
The t(11;22)(q24;q12) EWSR1/FLI1 is found in 85% of cases of Ewing tumours. The t(21;22)(q21;q12) with EWSR1/ERG is the second in frequency, found in about 10% of cases.
Hybrid gene
t(11;22)(q24;q12): 5 EWSR1 - 3 FLI1; breakpoints clustered over a 2-3 kb genomic region and over a 30-40 kb genomic region. Various junctions between EWSR1 exon 7 or 10 with FLI1 exon 5, 6, or 8. In the most common fusion type (type 1), EWSR1 exon 7 is fused in frame to FLI1 exon 6; in type 2, EWSR1 exon 7 is fused in frame to FLI1 exon 5. (Obata et al., 1999; de Alava et al., 1998).
t(21;22)(q21;q12): 5 EWSR1 - 3 ERG; the orientation of the ERG gene is from telomere to centromere, opposite to that demonstrated for EWSR1.
Other translocations: 5 EWSR1 - 3 FEV; 5 EWSR1 - 3 ETV1; 5 EWSR1 - 3 ETV4; 5 EWSR1 - 3 NFATC2; 5 EWSR1 - 3 PATZ1.
Fusion protein
t(11;22)(q24;q12): oncogenic protein on the der(22) chromosome generated by fusion of the N terminal domain of EWSR1 protein (transactivation domain, e.g. fusion of EWSR1 amino acids 1-265) with the DNA binding domain (ETS type, amino acids 281-361) of the human FLI1 protein, a 452 amino acids protein (e.g. fusion from amino acids 260).
t(21;22)(q21;q12): oncogenic protein on the der(22) chromosome generated by fusion of the N terminal domain of EWSR1 protein with DNA binding domain of human ERG protein.
Other translocations: Most of the EWSR1 partners in ES/PNET are ETS family members (FLI1, ERG, ETV1, ETV4, FEV) and translocation results in the juxtaposition of the transactivation domain of EWSR1 with the DNA binding domain -ETS type of the partner. PATZ1 is a transcription regulator with a AT hook (DNA-binding motif), a POZ domain (mediates dimerisation) and Zn fingers (DNA-binding). NFATC2 is a cytokine inducer; translocates into the nucleus to regulate transcription.
Oncogenesis
EWSR1-FLI1 is a dominant oncogene transformed cells by subverting normal transcriptional controls/FLI1 member of ETS family. The target gene repertoire of EWSR1-FLI1 varies according to the host cell type. EWSR1-FLI1 induces a TP53-dependent growth arrest in fibroblasts, supporting the importance of TP53 loss in the genesis of Ewings tumours (Lessnick et al., 2002). EWSR1-FLI1 activates CASP3 and promotes apoptosis in mouse embryonic fibroblasts (Sohn et al., 2010). EWSR1-FLI1 induces expression of the embryonic stem cell genes OCT4, SOX2, and NANOG in paediatric mesenchymal stem cells but not in adult mesenchymal stem cells. SOX2 is a target for EWSR1-FLI1 and miRNA145 and may be critical in Ewing sarcoma pathogenesis (Riggi et al., 2010). EWSR1-FLI1 expression in a rhabdomyosarcoma cell line induced upregulation of many genes involved in neural crest differentiation, and the cell phenotype was modified, resembling ewing tumour cells (Hu-Lieskovan et al., 2005; Riggi et al., 2008). EZH2 is a target of EWSR1-FLI1. EZH2 regulates stemness and genes involved in neuroectodermal and endothelial differentiation (Richter et al., 2009). EWSR1-FLI1 induced T-cell neoplasia in committed lymphoid cells, showing that the oncogenetic potential of EWSR1-FLI1 is not restricted to pluripotent progenitors or mesenchymal cells (Codrington et al., 2005). EWSR1-FLI1 in transgenic mouse induced limb developmental defects by disruption of the normal development of connective tissues; homozygous deletion of p53 in mice provoke sarcomas, in particular osteosarcomas, introduction of EWSR1-FLI1 changed the tumour phenotype from osteosarcomas to poorly differentiated sarcomas (Lin et al., 2008). It is believed that EW/PNET arise from mesenchymal stem cells in which terminal differentiation is blocked by EWSR1-FLI1 (Tirode et al., 2007).
Transcriptional repressors such as NKX2-2 (Smith et al., 2006) or NR0B1 are induced by EWSR1-FLI1. Furthermore, EWSR1-FLI and NR0B1 physically interact (Kinsey et al., 2009). The transcriptional complex of EWSR1-FLI1 includes RNA polymerase II, CREB1 (cAMP responsive element binding protein 1) and DHX9 (RHA, RNA helicase A) (Toretsky et al., 2006; Erkizan et al., 2009). EWSR1-Ets proteins cooperatively bind DNA with FOS-JUN (Kim et al., 2006). EWSR1-FLI1 is involved in the spliceosome (review in Erkizan et al., 2010). EWSR1-FLI1 chimeric protein, but not wild EWSR1, can oppose the change in splicing pattern induced by expression of hnRNPA1 (Knoop and Baker, 2001).
EWSR1-FLI1 (dis)regulates many pathways (Jedlicka, 2010). CD99, a transmembrane protein highly expressed in Ewing sarcoma cells, has a key role in various biological functions, including inhibition of neuronal differentiation that may occur through the RAS/RAF/MAPK pathway in Ewings tumours (Rocchi et al., 2010). PDGFC (Zwerner and May, 2001) as well as IGF1 are induced by EWSR1-FLI1, and also by EWSR1-ERG or FUS-ERG (Cironi et al., 2008). GLI1 is upregulated by EWSR1-FLI1, independently of the Hedgehog pathway (Beauchamp et al., 2009; Joo et al., 2009). Expression of DKK1 (which antagonizes Wnt signaling) is inhibited by EWSR1-FLI1 (Navarro et al., 2010), and DKK2 enhanced (Miyagawa et al., 2009). TGFbR2 is inhibited by EWSR1-FLI1 (Hahm, 1999).
Other features were summarized in Janknecht et al., 2005: EWSR1-FLI1 induces proliferation independent of exogenous growth factors (EWSR1-ETS proteins upregulate PDGFC and also CCND1), evasion of growth inhibition (downregulation of TGFbR2 may help cells escape growth surveillance), suppression of differentiation (ID2, overexpressed in Ewing tumours, is able to suppress differentiation of a variety of cells), immortality (hTERT (human telomerase reverse transcriptase)), limiting factor for telomerase activity and senescence, is upregulated by EWSR1-ETS fusion proteins), escape from apoptosis (EWSR1-FLI1 was shown to repress IGFBP-3, preventing apoptosis) (Janknecht et al., 2005).
Entity name
Desmoplastic small round cell sarcoma (DSRCT)
Note
- With: t(11;22)(p13;q12) --> WT1 - EWSR1 (Ladanyi and Gerald, 1994; Gerald et al., 1995; Benjamin et al., 1996; records in the Mitelman Database).
- With: t(21;22)(q21;q12) --> ERG - EWSR1 (Ordi et al., 1998).
Disease
Desmoplastic small round cell sarcoma is a small blue round cells tumour, often intra-abdominal, with a male predominance, arising in children and young adults, with a very poor prognosis. Cytogenetics and immunochemistry are essential for the differential diagnosis with other sarcomas with small blue round cells.
Cytogenetics
Most of the cases are cases of t(11;22)(p13;q12).
Hybrid gene
t(11;22)(p13;q12): 5 EWSR1 - 3 WT1; breakpoints: between EWSR1 exons 7 and 8 and between WT1 exons 7 and 8.
t(21;22)(q21;q12): 5 EWSR1 - 3 ERG.
Atlas Image
t(11;22)(q24;q12) G-banding (left) and R-banding (right) - Courtesy Francine Mugneret
Fusion protein
Transcription activator.
Oncogenesis
N terminal domain of EWSR1 fused to the Zn fingers of WT1.
Entity name
Clear cell sarcoma of soft parts/malignant melanoma of soft parts (CCSSP)
Note
- With: t(2;22)(q34;q12) --> CREB1 - EWSR1 (Antonescu et al., 2006; Wang et al., 2009).
- With: t(12;22)(q13;q12) --> ATF1 - EWSR1 (Zucman et al., 1993a; records in the Mitelman Database).
Disease
Clear cell sarcoma of tendons and aponeuroses affects young adults. It is characterized by slow progression, with recurrences and metastases, with only 40-50% long survivors.
Hybrid gene
5 EWSR1 - 3 ATF1 (t(12;22)(q13;q12) cases) or, more rarely, 5 EWSR1 - 3 CREB1 (t(2;22)(q33;q12) cases).
Fusion protein
N terminal domain of EWSR1 fused to the bZIP domain of CREB1 or ATF1.
Entity name
Angiomatoid fibrous histiocytoma (AFH)
Note
- With: t(2;22)(q34;q12) --> CREB1 - EWSR1 (Antonescu et al., 2007; Shao et al., 2009; Rossi et al., 2007).
- With: t(12;22)(q13;q12) --> ATF1 - EWSR1 (Dunham et al., 2008; Hallor et al., 2005; Hallor et al., 2007; Rossi et al., 2007; Tanas et al., 2010).
Note: Cases of t(12;16)(q13;p11) with 5 FUS - 3 ATF1 have also been described (Raddaoui et al., 2002; Waters et al., 2000).
Disease
Angiomatoid fibrous histiocytoma is a rare soft-tissue tumour of low metastatic potential (local recurrence below 15% of cases, and metastases occur in less than 2% of patients); it is mostly found in children and young adults. Surgical excision is the treatment of choice.
Hybrid gene
5 EWSR1 - 3 ATF1 (t(12;22)(q13;q12) cases), or 5 EWSR1 - 3 CREB1 (t(2;22)(q33;q12) cases).
Fusion protein
N terminal domain of EWSR1 fused to the bZIP domain of ATF1 or CREB1.
Entity name
Extraskeletal myxoid chondrosarcoma (EMCS)
Disease
Extra-skeletal myxoid chondrosarcomas represent about 5% of chondrosarcomas. There is male predominance. It affects adults mainly, in the forties or the fifties. The estimated 5-, 10-, and 15-year survival rates were 90%, 70%, and 60%, respectively (Meis-Kindblom et al., 1999).
Cytogenetics
t(9;22)(q22;q12) --> NR4A3 - EWSR1 (Labelle et al., 1995; Brody et al., 1997).
Note: Cases of t(3;9)(q12;q31) --> NR4A3 - TFG (Hisaoka et al., 2004), t(9;15)(q31;q21) --> NR4A3 - TCF12 (Sjögren et al., 2000), t(9;17)(q22;q11) --> NR4A3 - TAF15 (Sjögren et al., 1999; Attwooll et al., 1999; records in the Mitelman Database) have also been reported.
Hybrid gene
5 EWSR1 - 3 NR4A3 (NR4A3 is also known as TEC or CHN).
Entity name
Myxoid liposarcoma/round cell liposarcoma (MLS)
Disease
Myxoid liposarcoma is the most frequent type of liposarcoma, found in about half of the cases. It occurs in male and female patients equally, in their thirties to fifties. It has a relatively favorable prognosis; the variant round cell liposarcoma is much more aggressive.
Cytogenetics
A t(12;22)(q13;q12) --> DDIT3 - EWSR1 (Panagopoulos et al., 1994) is found in 5% of cases, whereas a t(12;16)(q13;p11) is found in most cases.
Hybrid gene
5 EWSR1 - 3 DDIT3 (also called CHOP). The t(12;16)(q13;p11) with 5 FUS - 3 DDIT3 is more frequent.
Fusion protein
Fuses the N-term transactivation domain of EWSR1 with the bZIP domain of DDIT3.
Entity name
Acute leukaemia
Disease
Acute lymphoblastic leukaemia (B-cell ALL), biphenotypic leukaemia
Cytogenetics
A t(12;22)(p13;q12) was found in 2 cases (Martini et al., 2002). Note: the equivalent t(12;17)(p13;q11) --> TAF15 - ZNF384 has also been found in other cases of the same series.
Hybrid gene
5 EWSR1 - 3 ZNF384.
Fusion protein
Fuses the N-term transactivation domain of EWSR1 with the leucine-serine rich-proline-nuclear localization signal-Kruppel-type C2H2 Zinc finger domains of ZNF384.
Note
EWSR1 involvement has also been described in a number of other tumours. In some instances, the diagnosis is unambiguous; in other cases, pathological diagnoses are difficult to reach, when the tumour is undifferentiated or polyphenotypic.
Entity name
Rhabdomyosarcoma (RMS)
Disease
Rhabdomyosarcomas, the most common pediatric soft tissue sarcomas, are tumours related to the skeletal muscle lineage. The 2 major subtypes are alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Most ARMS cases are characterised by either a t(2;13)(q35;q14), resulting in a PAX3 - FOXO1 hybrid gene, or a t(1;13)(p36;q14) resulting in a PAX7 - FOXO1 hybrid gene (Reichek and Barr, 2009). However, 4 cases of RMS have been described, instead, with an EWSR1 rearrangement.
Cytogenetics
A t(4;22)(q35;q12) was found in a case of embryonal rhabdomyosarcoma (Sirvent et al., 2009), and a t(11;22)(q24;q12) in the other cases (Sorensen et al., 1993; Thorner et al., 1996).
Hybrid gene
5 EWSR1 - 3 DUX4 in the t(4;22)(q35;q12) case, and 5 EWSR1 - 3 FLI1 in the t(11;22) cases.
Entity name
Giant cell tumour of bone
Disease
Locally destructive tumour, usually seen in patients over 20 years of age, with good prognosis, despite of recurrences and pulmonary metastases (Forsyth and Hogendoorn, 2003).
Cytogenetics
In giant-cell tumour of bone, the most frequent finding is telomeric association. One study showed that a very minor clone with EWSR1/FLI1 translocation could be detected in most of the cases studied (Scotlandi et al., 2000).
Hybrid gene
5 EWSR1 - 3 FLI1.
Entity name
Myoepithelioma/myoepithelial carcinoma of soft parts
Disease
Myoepithelioma tumours of soft tissue cover a wide range of tumours of various behaviour. While most are of intermediate aggressivity, some metastase.
Cytogenetics
t(1;22)(q23;q12) in one case (Brandal et al., 2008), t(19;22)(q13;q12) in another case (Brandal et al., 2009).
Hybrid gene
5 EWSR1 - 3 PBX1, which fuses exons 8 from EWSR1 to exons 5 of PBX1 in the most benign case; 5 EWSR1- 3 ZNF444 in the malignant case; fuses EWSR1 exon 8 to the very near end of ZNF444.
Entity name
Hidradenoma of the skin
Disease
Hidradenoma or eccrine/apocrine acrospiroma, is a benign adnexal tumour developing most often in adults. 3 cases were found with a t(6;22)(p21;q12) and/or its fusion transcript equivalent (Möller et al., 2008).
Fusion protein
5 EWSR1 - 3 POU5F1.
Entity name
Mucoepidermoid carcinoma of the salivary glands
Disease
Mucoepidermoid carcinoma is the most common type of malignant salivary gland tumour, often associated with a t(11;19)(q21;p13) translocation with expression of chimeric genes 5 CRTC1 - 3 MAML2. One case of mucoepidermoid carcinoma was found with a t(6;22)(p21;q12) (Möller et al., 2008).
Fusion protein
5 EWSR1 - 3 POU5F1.
Entity name
Neuroblastoma
Disease
Neuroblastomas are peripheral neuroblastic tumours derived from cells of the sympathetic nervous system. They occur mainly in infants and young children, with a median age of 1.5 years.
Hybrid gene
Two patients, aged 3 years and 5.5 years, were described with a 5 EWSR1 - 3 FLI1 transcript in typical neuroblastomas with elevated urinary catecholamines. Prognosis had been very poor: the two patients relapsed during -or at the end of- treatment and died within 2 months (Burchill et al., 1997).
Entity name
Olfactory neuroblastoma
Disease
Olfactory neuroblastoma or esthesioneuroblastoma, is a malignant neurectodermal tumour, from the olfactory neuroepithelium that typically occurs in the superior nasal cavity. It is keratin negative, neuroendocrine marker positive, and S100 positive. It arises at any age, often in the adult, with a 5-year survival rate above 50% (the 5-year overall survival for patients treated for nonmetastatic olfactory neuroblastoma was recently found at 64% (Ozsahin et al., 2010)).
Cytogenetics
t(11;22)(q24;q12), inducing a 5 EWSR1 - 3 FLI1 hybrid gene (Sorensen et al., 1996). However, recent review rejects cases with EWSR1 involvement, as being misdiagnosed cases of ES/PNET (Thompson, 2009).
Entity name
Solid pseudopapillary tumour of the pancreas (SPTP)
Disease
Solid pseudopapillary tumour of the pancreas is a rare epithelial tumour, typically occuring in young female patients, rarely metastasizing (Yu et al., 2010).
Cytogenetics
One case showed a t(11;22)(q24;q12) (Maitra et al., 2000)
Hybrid gene
5 EWSR1 - 3 FLI1.
Entity name
"Small round cell tumours", "polyphenotypic mesenchymal malignancies", and "undifferentiated sarcomas"
Disease
An undifferentiated sarcoma derived from pelvic bone exhibited a t(6;22)(p21;q12) with 5 EWSR1 - 3 POU5F1. This resulted in the fusion of exons 1-6 of EWSR1 and exons 2-5 and a part of exon 1 of POU5F1.The patient died 6 months after diagnosis (Yamaguchi et al., 2005).
A small round cell tumour was found to have a t(2;22)(q31;q12), with 5 EWSR1 - 3 SP3 hybrid gene; fuses the exon 7 of EWSR1 to exon 6 of SP3. N-term transactivation domain of EWSR1 fused with the Zinc fingers of SP3. The patient died 20 months after diagnosis (Wang et al., 2007).
Other cases of spindle cell tumours, small round cell poorly differentiated, biphenotypic (myogenic/neural differentiation), or polyphenotypic sarcomas present with the classical t(11;22)(q24;q12) / 5 EWSR1 - 3 FLI1 or other variants, such as the t(2;22)(q36;q12) / 5 EWSR1 - 3 FEV (Wang et al., 2007), the t(11;22)(p13;q12) / 5 EWSR1 - 3 WT1 (Alaggio et al., 2007), the t(12;22)(q13;q12) / 5 EWSR1 - 3 ATF1 (Somers et al., 2005), or the t(21;22)(q21;q12) / 5 EWSR1 - 3 ERG (Tan et al., 2001).

Breakpoints

Atlas Image

Note

Clustered over a 2.3 kb genomic region.

Article Bibliography

Pubmed IDLast YearTitleAuthors
173254882007Spindle cell tumor with EWS-WT1 transcript and a favorable clinical course: a variant of DSCT, a variant of leiomyosarcoma, or a new entity? Report of 2 pediatric cases.Alaggio R et al
86315011996A nuclear protein regulated during the transition from active to quiescent phenotype in cultured endothelial cells.Alliegro MC et al
186205642008The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response.Andersson MK et al
177247452007EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma.Antonescu CR et al
124595542003Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription.Araya N et al
114313762001The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1.Arvand A et al
106025201999Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma.Attwooll C et al
179123562007Ewing sarcoma protein ewsr1 maintains mitotic integrity and proneural cell survival in the zebrafish embryo.Azuma M et al
81646781994DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma.Bailly RA et al
191899742009GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein.Beauchamp E et al
129151282003Expression and subcellular localization of Ewing sarcoma (EWS) protein is affected by the methylation process.Belyanskaya LL et al
88270701996Fusion of the EWS1 and WT1 genes as a result of the t(11;22)(p13;q12) translocation in desmoplastic small round cell tumors.Benjamin LE et al
197376552009Ewing sarcoma-peripheral neuroectodermal tumor of the kidney with a FUS-ERG fusion transcript.Berg T et al
94884651998EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes.Bertolotti A et al
197606022009t(19;22)(q13;q12) Translocation leading to the novel fusion gene EWSR1-ZNF444 in soft tissue myoepithelial carcinoma.Brandal P et al
90608411997Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma.Brody RI et al
91354951997EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma.Burchill SA et al
113258242001Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein.Chansky HA et al
186485442008IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells.Cironi L et al
159748032005The Ews-ERG fusion protein can initiate neoplasia from lineage-committed haematopoietic cells.Codrington R et al
15229031992Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.Delattre O et al
93411881997The prooncoprotein EWS binds calmodulin and is phosphorylated by protein kinase C through an IQ domain.Deloulme JC et al
92422121997Multiple chromosomal mechanisms generate an EWS/FLI1 or an EWS/ERG fusion gene in Ewing tumors.Desmaze C et al
183008002008Primary intracerebral angiomatoid fibrous histiocytoma: report of a case with a t(12;22)(q13;q12) causing type 1 fusion of the EWS and ATF-1 genes.Dunham C et al
80763441994ERG gene is translocated in an Ewing's sarcoma cell line.Dunn T et al
205476962010Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma.Erkizan HV et al
150219032004The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1.Gascoyne DM et al
78626271995Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.Gerald WL et al
80403011994EWS-erg and EWS-Fli1 fusion transcripts in Ewing's sarcoma and primitive neuroectodermal tumors with variant translocations.Giovannini M et al
171069162006An in vitro enzymatic assay coupled to proteomics analysis reveals a new DNA processing activity for Ewing sarcoma and TAF(II)68 proteins.Guipaud O et al
105810421999Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein.Hahm KB et al
171884282007Fusion genes in angiomatoid fibrous histiocytoma.Hallor KH et al
104517051999Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors.Hattinger CM et al
151884552004TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.Hisaoka M et al
159302812005EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing's family of tumors.Hu-Lieskovan S et al
162025442005EWS-ETS oncoproteins: the linchpins of Ewing tumors.Janknecht R et al
89636221996An unusual cerebellar primitive neuroectodermal tumor with t(11;22) translocation: pathological and molecular analysis.Jay V et al
204903262010Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions.Jedlicka P et al
77006481995A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1.Jeon IS et al
198595632009GLI1 is a central mediator of EWS/FLI1 signaling in Ewing tumors.Joo J et al
90715761997EWS-ERG fusion transcript produced by chromosomal insertion in a Ewing sarcoma.Kaneko Y et al
88341751996Fusion of an ETS-family gene, EIAF, to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy.Kaneko Y et al
165378932006Cooperative DNA binding with AP-1 proteins is required for transformation by EWS-Ets fusion proteins.Kim S et al
199201882009EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma.Kinsey M et al
113013182001EWS/FLI alters 5'-splice site selection.Knoop LL et al
86346901995Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation.Labelle Y et al
81870631994Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor.Ladanyi M et al
167696712006TLS, EWS and TAF15: a model for transcriptional integration of gene expression.Law WJ et al
159174702005Stimulation of Oct-4 activity by Ewing's sarcoma protein.Lee J et al
191332752009Dynamic subcellular localization of the Ewing sarcoma proto-oncoprotein and its association with and stabilization of microtubules.Leemann-Zakaryan RP et al
120868532002The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts.Lessnick SL et al
174154122007Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development.Li H et al
189741412008EWS-FLI1 induces developmental abnormalities and accelerates sarcoma formation in a transgenic mouse model.Lin PP et al
109767202000Soft tissue Ewing sarcoma--peripheral primitive neuroectodermal tumor with atypical clear cell pattern shows a new type of EWS-FEV fusion transcript.Llombart-Bosch A et al
185253372008Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future.Ludwig JA et al
182956592008Complex rearrangement of chromosomes 19, 21, and 22 in Ewing sarcoma involving a novel reciprocal inversion-insertion mechanism of EWS-ERG fusion gene formation: a case analysis and literature review.Maire G et al
110003392000Detection of t(11;22)(q24;q12) translocation and EWS-FLI-1 fusion transcript in a case of solid pseudopapillary tumor of the pancreas.Maitra A et al
123597452002Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia.Martini A et al
109499352000A novel zinc finger gene is fused to EWS in small round cell tumor.Mastrangelo T et al
103661451999Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases.Meis-Kindblom JM et al
102094951998A novel EWS-ERG rearrangement generating two hybrid mRNAs in a peripheral primitive neuroectodermal tumour (pPNET) with a t(15;22) translocation.Minoletti F et al
192474492009EWS/ETS regulates the expression of the Dickkopf family in Ewing family tumor cells.Miyagawa Y et al
183383302008POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands.Möller E et al
200190922010The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes beta-catenin/TCF-mediated transcription.Navarro D et al
118545962002Atypical pleomorphic extraosseous ewing tumor/peripheral primitive neuroectodermal tumor with unusual phenotypic/genotypic profile.Navarro S et al
102213341999Molecular characterization of the genomic breakpoint junction in a t(11;22) translocation in Ewing sarcoma.Obata K et al
97069841998Intraabdominal desmoplastic small round cell tumor with EWS/ERG fusion transcript.Ordi J et al
202310622010Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study.Ozsahin M et al
79878491994Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation.Panagopoulos I et al
98453641998A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing.Pellizzoni L et al
114066512001A multiplex real-time pcr assay for the detection of gene fusions observed in solid tumors.Peter M et al
87074061996An EWS/ERG fusion with a truncated N-terminal domain of EWS in a Ewing's tumor.Peter M et al
83075701993Genomic structure of the EWS gene and its relationship to EWSR1, a site of tumor-associated chromosome translocation.Plougastel B et al
122184552002Fusion of the FUS and ATF1 genes in a large, deep-seated angiomatoid fibrous histiocytoma.Raddaoui E et al
192898322009EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation.Richter GH et al
203827292010EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.Riggi N et al
201976222010CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis.Rocchi A et al
199367822010Soft tissue tumors associated with EWSR1 translocation.Romeo S et al
180944132007EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma.Rossi S et al
112891492001The Ewing's sarcoma gene product functions as a transcriptional activator.Rossow KL et al
108970362000Identification of EWS/FLI-1 transcripts in giant-cell tumor of bone.Scotlandi K et al
186668232009Angiomatoid fibrous histiocytoma with t(2;22)(q33;q12.2) and EWSR1 gene rearrangement.Shao L et al
129076332003FUS/ERG gene fusions in Ewing's tumors.Shing DC et al
198372622009Fusion of EWSR1 with the DUX4 facioscapulohumeral muscular dystrophy region resulting from t(4;22)(q35;q12) in a case of embryonal rhabdomyosarcoma.Sirvent N et al
105372741999Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid chondrosarcoma.Sjögren H et al
111563742000Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21).Sjögren H et al
166979602006Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma.Smith R et al
201036432010EWS/FLI1 oncogene activates caspase 3 transcription and triggers apoptosis in vivo.Sohn EJ et al
163274422005Association of the t(12;22)(q13;q12) EWS/ATF1 rearrangement with polyphenotypic round cell sarcoma of bone: a case report.Somers GR et al
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121834112002Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway.Spahn L et al
193184792009The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology.Szuhai K et al
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198019662010Utility of FISH in the diagnosis of angiomatoid fibrous histiocytoma: a series of 18 cases.Tanas MR et al
191228072008TFIP11, CCNL1 and EWSR1 Protein-protein Interactions, and Their Nuclear Localization.Tannukit S et al
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205969812009Olfactory neuroblastoma.Thompson LD et al
86448551996Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types.Thorner P et al
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Other Information

Locus ID:

NCBI: 2130
MIM: 133450
HGNC: 3508
Ensembl: ENSG00000182944

Variants:

dbSNP: 2130
ClinVar: 2130
TCGA: ENSG00000182944
COSMIC: EWSR1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000182944ENST00000331029B0QYK0
ENSG00000182944ENST00000332035Q01844
ENSG00000182944ENST00000332050C9JGE3
ENSG00000182944ENST00000333395Q01844
ENSG00000182944ENST00000360091H7BY36
ENSG00000182944ENST00000397938Q01844
ENSG00000182944ENST00000406548Q01844
ENSG00000182944ENST00000414183Q01844
ENSG00000182944ENST00000415761B0QYJ6
ENSG00000182944ENST00000436425B0QYJ3
ENSG00000182944ENST00000437155F8WC90
ENSG00000182944ENST00000444626B0QYJ5
ENSG00000182944ENST00000447973B0QYJ4
ENSG00000182944ENST00000455726B0QYJ7
ENSG00000182944ENST00000629659A0A0D9SFL3

Expression (GTEx)

0
50
100
150
200
250
300
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

References

Pubmed IDYearTitleCitations
381581262024EWSR1::WT1 Fusions in Neoplasms Other Than Conventional Desmoplastic Small Round Cell Tumor: Three Tumors Occurring Outside the Female Genital Tract.0
381680932024Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions.0
382542072024Report and literature review of four cases of EWSR1::NFATC2 round cell sarcoma.0
383390142024Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms.0
385061122024Endogenous EWSR1 Exists in Two Visual Modalities That Reflect Its Associations with Nucleic Acids and Concentration at Sites of Active Transcription.0
385118742024Ewing Sarcoma Related protein 1 recognizes R-loops by binding DNA forks.0
385884092024Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.0
386398532024Central nervous system embryonal tumors with EWSR1-PLAGL1 rearrangements reclassified as INI-1 deficient tumors at relapse.0
381581262024EWSR1::WT1 Fusions in Neoplasms Other Than Conventional Desmoplastic Small Round Cell Tumor: Three Tumors Occurring Outside the Female Genital Tract.0
381680932024Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions.0
382542072024Report and literature review of four cases of EWSR1::NFATC2 round cell sarcoma.0
383390142024Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms.0
385061122024Endogenous EWSR1 Exists in Two Visual Modalities That Reflect Its Associations with Nucleic Acids and Concentration at Sites of Active Transcription.0
385118742024Ewing Sarcoma Related protein 1 recognizes R-loops by binding DNA forks.0
385884092024Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.0

Citation

Jean-Loup Huret

EWSR1 (Ewing sarcoma breakpoint region 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-08-01

Online version: http://atlasgeneticsoncology.org/gene/85/img/teaching-explorer/js/_common.js

Historical Card

1998-04-01 EWSR1 (Ewing sarcoma breakpoint region 1) by  Francine Mugneret 

Laboratoire de Cytogénétique, CHU Le Bocage, BP 77908, 21079 Dijon Cedex, France