* 133450

EWS RNA-BINDING PROTEIN 1; EWSR1


Alternative titles; symbols

EWING SARCOMA BREAKPOINT REGION 1
EWS GENE; EWS


Other entities represented in this entry:

EWS/FLI1 FUSION GENE, INCLUDED
EWS/ERG FUSION GENE, INCLUDED
EWS/WT1 FUSION GENE, INCLUDED
EWS/ATF1 FUSION GENE, INCLUDED
EWS/FEV FUSION GENE, INCLUDED
EWS/ZNF278 FUSION GENE, INCLUDED
EWS/CREB1 FUSION GENE, INCLUDED
EWS/NR4A3 FUSION GENE, INCLUDED
EWS/POU5F1 FUSION GENE, INCLUDED
EWS/ETV1 FUSION GENE, INCLUDED
EWS/ETV4 FUSION GENE, INCLUDED
EWS/UQCRH FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: EWSR1

Cytogenetic location: 22q12.2     Genomic coordinates (GRCh38): 22:29,268,268-29,300,521 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
22q12.2 Ewing sarcoma 612219 3
Neuroepithelioma 612219 3

TEXT

Cloning and Expression

The EWS gene was identified based on its location at the chromosome 22 breakpoint of the t(11;22)(q24;q12) translocation that characterizes Ewing sarcoma and related neuroectodermal tumors (see 612219). Phylogenetically conserved restriction fragments in the vicinity of the breakpoints on chromosomes 22 and 11 allowed identification of transcribed sequences from these regions and indicated that a hybrid transcript might be generated by the translocation (Zucman et al., 1992). Delattre et al. (1992) screened cDNA libraries with these conserved fragments and found that the translocation alters the open reading frame of an expressed gene, EWS, on chromosome 22 by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the FLI1 gene (193067). The EWS protein encodes 656 amino acids. The N terminus contains a repeated degenerated polypeptide of 7 to 12 residues rich in tyrosine, serine, threonine, glycine, and glutamine, and the C terminus contains 3 arginine- and glycine-rich tracts and a putative RNA-binding domain. Plougastel et al. (1994) found that the human and mouse proteins share 98% sequence homology.

Ohno et al. (1994) demonstrated differential splicing of the EWS protein involving 2 exons encoding 72 amino acids. Both alternatively spliced transcripts are expressed in a variety of cells.


Evolution

Aman et al. (1996) reported that the exon/intron structures of FUS (137070) and EWS show extensive similarities in the RNP regions and suggested that the 2 genes may have been derived from a common ancestor. Morohoshi et al. (1998) noted that the conservation of the overall exon number and structure of RBP56 (601574), FUS/TLS, and EWS indicates that they probably originated from the same ancestral gene.


Gene Structure

Plougastel et al. (1993) demonstrated that the EWS gene spans about 40 kb of DNA and has 17 exons. The first 7 exons encode the N-terminal domain, and exons 11, 12, and 13 encode the putative RNA-binding domain.


Mapping

Delattre et al. (1992) identified the EWS gene at the chromosome 22 breakpoint of the t(11;22)(q24;q12) translocation that characterizes Ewing sarcoma. Plougastel et al. (1994) identified the mouse Ews gene within a segment of chromosome 11 that shows syntenic homology with human 22q12.


Gene Function

Ohno et al. (1994) showed that one of the EWS transcripts binds to RNA in vitro, and specifically to poly-G and poly-U. The RNA-binding activity was localized to the C-terminal 86 amino acids that constitute an RGG box. Thus, the N-terminal domain of EWS, which is involved in chromosome translocation, may regulate the specificity of RNA-binding activity of EWS. By mutation analysis of the EWS/ERG chimeric protein, Ohno et al. (1994) found that the N-terminal EWS functions as a regulatory domain for the transcriptional activation properties of the chimeric protein.

Aman et al. (1996) noted that although the N-terminal ends of FUS (137070) and EWS are different, they share extensive homology and are distinct from the N-terminal regions of other RNP-carrying proteins. They proposed that FUS and EWS may be regarded as the first members of a new family of RNA-binding proteins. Aman et al. (1996) stressed that the nature of the promoter regions of FUS and EWS is important for understanding the control of the fusion genes involving FUS and EWS in tumors. All of the tumor-specific translocations lead to the formation of fusion genes with FUS or EWS promoter regions and 5-prime coding regions linked to transcription factor genes. Aman et al. (1996) concluded that the transcriptional control of the fusion genes is most likely dominated by the FUS and EWS promoters.

The N-terminal region of the EWS gene has been found to be fused with the DNA-binding domain of several different transcription factors, leading to various human malignancies.

EWS/FLI1 FUSION GENE

May et al. (1993) showed that the 11;22 translocation of Ewing sarcoma produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 (193067) for transformation. Plougastel et al. (1993) found that of 19 Ewing tumors, the chromosome 22 breakpoint was localized in intron 7 or 8 in 18 cases and in intron 10 in 1 case.

Using a competitive PCR technique, Tanaka et al. (1997) showed that there might be a correlation between the expression levels of the EWS/FLI1 fusion gene and the proliferative activity of Ewing sarcoma and primitive neuroectodermal tumor cells. Furthermore, when the EWS/FLI1 expression was inhibited by antisense oligodeoxynucleotides against the fusion RNA, the growth of tumor cells was significantly reduced both in vitro and in vivo. Their data further indicated that the growth inhibition of the cells by the antisense sequence might be mediated by G0/G1 block in the cell cycle progression. Burchill et al. (1997) used RT-PCR for evaluation of EWS/FLI1 fusion transcripts in 18 neurally derived small round cell tumors. These included 6 tumors of the Ewing family and 12 neuroblastomas. EWS/FLI1 fusion transcripts were identified in all 6 Ewing tumors, but also in 2 of the 12 neuroblastomas.

Lin et al. (1999) stated that the translocation resulting in the formation of the EWS/FLI1 fusion gene is present in up to 95% of cases of Ewing sarcoma. Alternative forms of the chimeric gene exist because of variations in the locations of the EWS and FLI1 genomic breakpoints. The most common form, designated type 1, consists of the first 7 exons of EWS joined to exons 6-9 of FLI1 and accounts for approximately 60% of cases. The type 2 EWS/FLI1 fusion includes FLI1 exon 5 also and is present in another 25%. Lin et al. (1999) observed that the type 1 fusion is associated with a significantly better prognosis than the other fusion types. They found that the type 1 EWS/FLI1 fusion encodes a less active chimeric transcription factor, thus providing a molecular explanation of clinical heterogeneity in Ewing sarcoma.

By electrophoretic mobility shift assays, Nakatani et al. (2003) found that EWS/FLI1 interacted with the ETS consensus sequence within the promoter region of the p21(WAF1) gene (CDKN1A; 116899). Reporter gene assays indicated that the binding of EWS/FLI1 to at least 2 ETS binding sites negatively regulated p21(WAF1) promoter activity. EWS/FLI1 also suppressed p21(WAF1) induction by interacting with p300 (602700) and inhibiting its histone acetyltransferase activity.

EWS/ERG FUSION GENE

Bielack et al. (2004) described a 14-year-old girl without a family history of cancer who initially presented with a Ewing sarcoma of the atlas in which they identified a chimeric EWS/ERG (165080) fusion transcript characteristic of the t(21;22)(q22;q21) translocation. Four and a half years later, the girl was found to have a second Ewing sarcoma, of the right proximal humerus, in which an EWS/FLI1 type 5 translocation was identified. Bielack et al. (2004) stated that this was the first report of such molecular heterogeneity in specimens of Ewing sarcoma from a single patient.

EWS/ATF1 FUSION GENE

Just as the fusion of the 5-prime portion of the EWS gene to the FLI1 gene results in Ewing sarcoma, fusion of the same part of the EWS gene to the ATF1 gene (123803) results in malignant melanoma of soft parts (MMSP) (Zucman et al., 1993).

In tumor tissue derived from a patient with angiomatoid fibrous histiocytoma (612160), Hallor et al. (2005) identified a t(12;22)(q13;q12) translocation. RT-PCR analysis detected an EWS/ATF1 fusion gene between exons 7 and 5, respectively, that functioned as a constitutive transcriptional activator.

In a tumor sample from a patient with angiomatoid fibrous histiocytoma, Antonescu et al. (2007) identified an EWSR1/ATF1 fusion gene linking exon 7 of EWSR1 to exon 5 of ATF1.

EWS/WT1 FUSION GENE

Desmoplastic small round cell tumor (DSRCT) is associated with a recurrent chromosomal translocation, t(11;22)(p13;q12). DSRCT is characterized by a predilection for young males, abdominal serosal involvement, poor prognosis, and a primitive histologic appearance. Because the recurrent chromosome translocation breakpoints in t(11;22)(p13;q12) associated with desmoplastic small round cell tumor are located cytogenetically in the regions of 2 tumor-associated genes, WT1 (607102) on chromosome 11 and EWS on chromosome 22, Gerald et al. (1995) investigated these genes as potential translocation partners in DSRCT and showed that they are consistently rearranged in genomic DNA isolated from tumor tissue. The breakpoints involved the intron between EWS exons 7 and 8 and the intron between WT1 exons 7 and 8. Chimeric transcripts corresponding to the fusion gene were detected in 4 of 6 cases studied. Analyses of these transcripts showed an in-frame fusion of RNA encoding the N-terminal domain of EWS to both alternatively spliced forms of the last 3 zinc fingers of the DNA-binding domain of WT1. Thus, DSRCT represents another tumor type associated with translocation of EWS; it is the first tumor associated with a consistent translocation involving WT1. The chimeric products were predicted to modulate transcription at WT1 target sites and contribute to the development of this unique tumor.

EWS/ETV1 FUSION GENE

Jeon et al. (1995) identified a variant type of Ewing sarcoma translocation, t(7;22)(p22;q12), that fused EWS to the ETV1 gene (600541).

Wang et al. (2007) reported 2 unrelated children with small round cell tumors harboring an EWS/ETV1 fusion gene resulting from the fusion of exon 7 to exon 10 or 11 in the 2 genes, respectively. Both were soft tissue tumors.

EWS/FEV FUSION GENE

Peter et al. (1997) described a t(2;22) translocation that fused the N-terminal transcription-activation domain of EWS to the ETS DNA-binding domain of FEV (607150) in a paraspinal tumor in a 2-year-old girl and in an extraosseous maxillary tumor in a 15-year-old boy. Sequence analysis indicated that exon 10 of EWS was linked in-frame to FEV.

Wang et al. (2007) identified a somatic EWS/FEV fusion gene in tissue derived from a 40-year-old man with a soft tissue tumor. The fusion joined exon 7 of EWS to exon 2 of FEV.

EWS/ZNF278 FUSION GENE

Mastrangelo et al. (2000) described a submicroscopic inversion of chromosome 22q in a small round cell sarcoma with a t(1;22)(p36.1;q12) translocation. The resultant chimeric transcript contained exon 8 of the EWS gene fused in-frame to exon 1 of the ZNF278 gene (605165), creating a protein with the transactivation domain of EWS fused to the zinc finger domain of ZNF278. Mastrangelo et al. (2000) found that the ZNF278 gene is located 2 Mb distal to EWS and is transcribed in the opposite orientation. Thus, they concluded that a paracentric inversion of 22q12 occurred to create the active EWS/ZNF278 fusion gene.

EWS/UQCRH FUSION GENE

Modena et al. (2003) characterized a translocation t(1;22)(p34;q12) that was associated with a paracentric inversion of chromosome 22q12 in a small round cell sarcoma. They had previously shown (Mastrangelo et al., 2000) that the inversion of chromosome 22q12 generated an EWS/ZSG (ZNF278; 605165) fusion gene. Modena et al. (2003) found that the t(1;22)(p34;q12) interrupted the UQCRH gene (613844), with the breakpoint in intron 3, and created fusion genes with both EWS on der(22) and ZSG on der(1). PCR analysis of tumor cDNA and genomic DNA detected 5-prime-UQCRH/EWS-3-prime, 5-prime-ZSG/UQCRH-3-prime, and 5-prime-EWS/ZSG-3-prime. Only 5-prime-EWS/ZSG-3-prime produced in-frame transcripts. In contrast, 5-prime-UQCRH/EWS-3-prime and 5-prime-ZSG/UQCRH-3-prime produced out-of-frame transcripts containing premature stop codons.

EWS/NR4A3 FUSION GENE

In tumor tissue derived from a patient with extraskeletal myxoid chondrosarcoma (EMC; 612237), Gill et al. (1995) demonstrated that a t(9;22)(q22-31;q11-12) translocation led to fusion of the EWS gene with a DNA segment from 9q22-q31. This particular t(9;22) was a recurrent cytogenetic finding in the myxoid variant of chondrosarcoma.

Panagopoulos et al. (2002) studied 18 cases of extraskeletal myxoid chondrosarcoma both cytogenetically and molecularly. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-q12, the sites of the NR4A3 (CHN) (600542) and EWS genes, respectively, and 3 with rearrangements involving 9q22 and 17q11, the sites of the NR4A3 and RBP56 genes (601574), respectively. An EWS/NR4A3 fusion transcript was found in 15 cases, and an RBP56/NR4A3 transcript in 3. The most frequent EWS/NR4A3 fusion transcript, present in 10 tumors, involved fusion of EWS exon 12 with NR4A3 exon 3; the second most common, present in 2 cases, was fusion of EWS exon 13 with NR4A3 exon 3.

Using a yeast functional complementation assay to identify possible functions of the EWS/NR4A3 (NOR1) fusion gene, Ohkura et al. (2002) determined that the EWS/NR4A3 fusion gene gains a novel activity affecting RNA. EWS/NR4A3 partially functioned as an snRNP in yeast and affected pre-mRNA splicing in mammalian cells. Mammalian cell studies showed that the EWS/NR4A3 fusion gene localized within the nucleus and showed characteristics similar to that of an RNA-binding protein. Overexpression of EWS/NR4A3 in mammalian cells resulted in increased usage of the distal 5-prime splice site of pre-mRNA splicing and that EWS/NR4A3 interacted with the U1C splicing protein. The findings suggested an oncogenic mechanism alternative to that of transcriptional control, and indicated that changes in pre-mRNA splicing may contribute to oncogenesis.

EWS/CREB1 Fusion Gene

In tumor tissue samples from 8 unrelated patients with angiomatoid fibrous histiocytoma (612160), Antonescu et al. (2007) identified an identical EWSR1/CREB1 (123810) fusion transcript with exon 7 of EWSR1 fused to exon 7 of CREB1. Antonescu et al. (2007) concluded that the EWSR1/CREB1 fusion gene is the most common genetic abnormality in this tumor type.

EWS/POU5F1 Fusion Gene

Yamaguchi et al. (2005) identified a t(6;22)(p21;q12) translocation in tumor tissue derived from an undifferentiated sarcoma from the pelvic bone of a 39-year-old woman. The translocation resulted in an EWS/POU5F1 chimeric gene composed of the N-terminal domain of EWS that functions as a transcriptional activation domain and the C-terminal DNA-binding domain of POU5F1. The authors suggested that the tumor may be variant of Ewing sarcoma.

EWS/SP3 Fusion Gene

Wang et al. (2007) identified an EWS/SP3 (601804) fusion gene in tumor tissue derived from a 16-year-old boy with an extraskeletal undifferentiated small round cell tumor. He had lesions in the extradural region, lung, and kidney. The EWS amino-terminal domain was fused to a zinc finger DNA-binding domain of SP3.

EWS/ETV4 Fusion Gene

Kaneko et al. (1996) identified a somatic t(17;22)(q12;q12) translocation in a MIC2 (CD99; 313470) antigen-positive undifferentiated sarcoma of infancy. On Southern blot analysis, EWS and E1AF (600711) cDNA probes hybridized to the same rearranged band, indicating that an EWS/E1AF fusion gene was formed in the tumor. Further Southern blot analysis showed that the breakpoint was in the region upstream to the ETS domain of the E1AF gene. Kaneko et al. (1996) concluded that the RNA binding domain of EWS may have been replaced by the DNA binding domain of E1AF in the EWS/E1AF fusion protein as in other fusion proteins previously characterized in various forms of Ewing sarcoma (612219).

Urano et al. (1996) identified a chimeric gene between the transactivation domain of EWS and E1AF in an extraskeletal Ewing sarcoma.

In the Ewing sarcoma tumors described by Kaneko et al. (1996) and Urano et al. (1996), Ishida et al. (1998) determined that the chimeric transcript represented an in-frame fusion between the 5-prime terminal region of EWSR1 and the 3-prime end of ETV4. The chimeric transcript could thus serve as a template for expression of a protein composed of the N-terminal portion of EWSR1 fused to the DNA-binding domain of ETV4. Long PCR and sequence analysis of genomic DNA revealed that either exon 8 or intron 7 of EWSR1 was fused to the same intron of ETV4 in both tumors. The 159-bp Alu-like sequence was repeated in the breakpoint region of the ETV4 gene, suggesting a mechanism of EWSR1/ETV4 gene fusion.


Genotype/Phenotype Correlations

In a review of 12 cases of unusual EWS fusion genes, Wang et al. (2007) concluded that tumors with EWS fusion to ETV1, ETV4, FEV, and SP3 tended to have strong predilection for extraskeletal primary sites. The tumors were often small round cell sarcomas of uncertain lineage.


Animal Model

Li et al. (2007) found that Ews +/- mice were indistinguishable from wildtype littermates and developed normally. Ews -/- pups were obtained at the expected mendelian ratio, but they were runted, and about 90% died prior to weaning, despite normal appearance of all major organs and normal suckling in most of the animals. Analysis of Ews -/- lymphocytes revealed a defect in pre-B cell development. During meiosis, Ews -/- spermatocytes were deficient in XY bivalent formation and showed reduced meiotic recombination, resulting in massive apoptosis and complete arrest in gamete maturation. Ews -/- fibroblasts showed premature cellular senescence, and Ews -/- animals were hypersensitive to ionizing radiation. Li et al. (2007) showed that Ews interacted with lamin A/C (LMNA; 150330), and loss of Ews resulted in reduced lamin A/C expression. Li et al. (2007) concluded that EWS has an essential role in pre-B cell development and meiosis and is involved in cellular senescence, and they proposed a role for EWS in DNA pairing and recombination/repair mechanisms.


REFERENCES

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Patricia A. Hartz - updated : 3/28/2011
Cassandra L. Kniffin - updated : 8/14/2008
Carol A. Bocchini - updated : 8/5/2008
Cassandra L. Kniffin - updated : 7/3/2008
Ada Hamosh - updated : 3/7/2008
Patricia A. Hartz - updated : 10/31/2007
Patricia A. Hartz - updated : 6/30/2005
Marla J. F. O'Neill - updated : 3/30/2004
Victor A. McKusick - updated : 1/14/2003
Patricia A. Hartz - updated : 8/15/2002
Paul J. Converse - updated : 7/14/2000
Victor A. McKusick - updated : 10/26/1999
Victor A. McKusick - updated : 9/3/1997
Victor A. McKusick - updated : 2/20/1997
Moyra Smith - updated : 12/13/1996
Creation Date:
Victor A. McKusick : 6/4/1986
carol : 09/11/2023
alopez : 06/13/2022
carol : 01/26/2021
terry : 04/04/2013
terry : 6/7/2012
terry : 4/26/2011
terry : 4/26/2011
mgross : 3/28/2011
carol : 8/20/2008
ckniffin : 8/14/2008
carol : 8/12/2008
carol : 8/5/2008
wwang : 7/8/2008
ckniffin : 7/3/2008
alopez : 3/20/2008
alopez : 3/20/2008
terry : 3/7/2008
mgross : 11/1/2007
terry : 10/31/2007
wwang : 6/30/2005
carol : 4/16/2004
tkritzer : 4/1/2004
terry : 3/30/2004
joanna : 3/16/2004
joanna : 11/6/2003
joanna : 9/23/2003
carol : 5/20/2003
carol : 5/20/2003
carol : 5/20/2003
carol : 1/21/2003
tkritzer : 1/16/2003
terry : 1/14/2003
ckniffin : 10/3/2002
ckniffin : 8/26/2002
mgross : 8/23/2002
mgross : 8/15/2002
mgross : 7/14/2000
mcapotos : 2/7/2000
carol : 10/27/1999
terry : 10/26/1999
carol : 8/25/1998
terry : 7/24/1998
terry : 5/29/1998
terry : 9/8/1997
terry : 9/3/1997
terry : 8/12/1997
mark : 2/20/1997
terry : 2/13/1997
mark : 12/13/1996
jenny : 12/9/1996
mark : 12/9/1996
mark : 5/21/1995
carol : 3/3/1995
mimadm : 9/24/1994
carol : 9/10/1993
carol : 7/6/1993
carol : 1/11/1993

* 133450

EWS RNA-BINDING PROTEIN 1; EWSR1


Alternative titles; symbols

EWING SARCOMA BREAKPOINT REGION 1
EWS GENE; EWS


Other entities represented in this entry:

EWS/FLI1 FUSION GENE, INCLUDED
EWS/ERG FUSION GENE, INCLUDED
EWS/WT1 FUSION GENE, INCLUDED
EWS/ATF1 FUSION GENE, INCLUDED
EWS/FEV FUSION GENE, INCLUDED
EWS/ZNF278 FUSION GENE, INCLUDED
EWS/CREB1 FUSION GENE, INCLUDED
EWS/NR4A3 FUSION GENE, INCLUDED
EWS/POU5F1 FUSION GENE, INCLUDED
EWS/ETV1 FUSION GENE, INCLUDED
EWS/ETV4 FUSION GENE, INCLUDED
EWS/UQCRH FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: EWSR1

Cytogenetic location: 22q12.2     Genomic coordinates (GRCh38): 22:29,268,268-29,300,521 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
22q12.2 Ewing sarcoma 612219 3
Neuroepithelioma 612219 3

TEXT

Cloning and Expression

The EWS gene was identified based on its location at the chromosome 22 breakpoint of the t(11;22)(q24;q12) translocation that characterizes Ewing sarcoma and related neuroectodermal tumors (see 612219). Phylogenetically conserved restriction fragments in the vicinity of the breakpoints on chromosomes 22 and 11 allowed identification of transcribed sequences from these regions and indicated that a hybrid transcript might be generated by the translocation (Zucman et al., 1992). Delattre et al. (1992) screened cDNA libraries with these conserved fragments and found that the translocation alters the open reading frame of an expressed gene, EWS, on chromosome 22 by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the FLI1 gene (193067). The EWS protein encodes 656 amino acids. The N terminus contains a repeated degenerated polypeptide of 7 to 12 residues rich in tyrosine, serine, threonine, glycine, and glutamine, and the C terminus contains 3 arginine- and glycine-rich tracts and a putative RNA-binding domain. Plougastel et al. (1994) found that the human and mouse proteins share 98% sequence homology.

Ohno et al. (1994) demonstrated differential splicing of the EWS protein involving 2 exons encoding 72 amino acids. Both alternatively spliced transcripts are expressed in a variety of cells.


Evolution

Aman et al. (1996) reported that the exon/intron structures of FUS (137070) and EWS show extensive similarities in the RNP regions and suggested that the 2 genes may have been derived from a common ancestor. Morohoshi et al. (1998) noted that the conservation of the overall exon number and structure of RBP56 (601574), FUS/TLS, and EWS indicates that they probably originated from the same ancestral gene.


Gene Structure

Plougastel et al. (1993) demonstrated that the EWS gene spans about 40 kb of DNA and has 17 exons. The first 7 exons encode the N-terminal domain, and exons 11, 12, and 13 encode the putative RNA-binding domain.


Mapping

Delattre et al. (1992) identified the EWS gene at the chromosome 22 breakpoint of the t(11;22)(q24;q12) translocation that characterizes Ewing sarcoma. Plougastel et al. (1994) identified the mouse Ews gene within a segment of chromosome 11 that shows syntenic homology with human 22q12.


Gene Function

Ohno et al. (1994) showed that one of the EWS transcripts binds to RNA in vitro, and specifically to poly-G and poly-U. The RNA-binding activity was localized to the C-terminal 86 amino acids that constitute an RGG box. Thus, the N-terminal domain of EWS, which is involved in chromosome translocation, may regulate the specificity of RNA-binding activity of EWS. By mutation analysis of the EWS/ERG chimeric protein, Ohno et al. (1994) found that the N-terminal EWS functions as a regulatory domain for the transcriptional activation properties of the chimeric protein.

Aman et al. (1996) noted that although the N-terminal ends of FUS (137070) and EWS are different, they share extensive homology and are distinct from the N-terminal regions of other RNP-carrying proteins. They proposed that FUS and EWS may be regarded as the first members of a new family of RNA-binding proteins. Aman et al. (1996) stressed that the nature of the promoter regions of FUS and EWS is important for understanding the control of the fusion genes involving FUS and EWS in tumors. All of the tumor-specific translocations lead to the formation of fusion genes with FUS or EWS promoter regions and 5-prime coding regions linked to transcription factor genes. Aman et al. (1996) concluded that the transcriptional control of the fusion genes is most likely dominated by the FUS and EWS promoters.

The N-terminal region of the EWS gene has been found to be fused with the DNA-binding domain of several different transcription factors, leading to various human malignancies.

EWS/FLI1 FUSION GENE

May et al. (1993) showed that the 11;22 translocation of Ewing sarcoma produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 (193067) for transformation. Plougastel et al. (1993) found that of 19 Ewing tumors, the chromosome 22 breakpoint was localized in intron 7 or 8 in 18 cases and in intron 10 in 1 case.

Using a competitive PCR technique, Tanaka et al. (1997) showed that there might be a correlation between the expression levels of the EWS/FLI1 fusion gene and the proliferative activity of Ewing sarcoma and primitive neuroectodermal tumor cells. Furthermore, when the EWS/FLI1 expression was inhibited by antisense oligodeoxynucleotides against the fusion RNA, the growth of tumor cells was significantly reduced both in vitro and in vivo. Their data further indicated that the growth inhibition of the cells by the antisense sequence might be mediated by G0/G1 block in the cell cycle progression. Burchill et al. (1997) used RT-PCR for evaluation of EWS/FLI1 fusion transcripts in 18 neurally derived small round cell tumors. These included 6 tumors of the Ewing family and 12 neuroblastomas. EWS/FLI1 fusion transcripts were identified in all 6 Ewing tumors, but also in 2 of the 12 neuroblastomas.

Lin et al. (1999) stated that the translocation resulting in the formation of the EWS/FLI1 fusion gene is present in up to 95% of cases of Ewing sarcoma. Alternative forms of the chimeric gene exist because of variations in the locations of the EWS and FLI1 genomic breakpoints. The most common form, designated type 1, consists of the first 7 exons of EWS joined to exons 6-9 of FLI1 and accounts for approximately 60% of cases. The type 2 EWS/FLI1 fusion includes FLI1 exon 5 also and is present in another 25%. Lin et al. (1999) observed that the type 1 fusion is associated with a significantly better prognosis than the other fusion types. They found that the type 1 EWS/FLI1 fusion encodes a less active chimeric transcription factor, thus providing a molecular explanation of clinical heterogeneity in Ewing sarcoma.

By electrophoretic mobility shift assays, Nakatani et al. (2003) found that EWS/FLI1 interacted with the ETS consensus sequence within the promoter region of the p21(WAF1) gene (CDKN1A; 116899). Reporter gene assays indicated that the binding of EWS/FLI1 to at least 2 ETS binding sites negatively regulated p21(WAF1) promoter activity. EWS/FLI1 also suppressed p21(WAF1) induction by interacting with p300 (602700) and inhibiting its histone acetyltransferase activity.

EWS/ERG FUSION GENE

Bielack et al. (2004) described a 14-year-old girl without a family history of cancer who initially presented with a Ewing sarcoma of the atlas in which they identified a chimeric EWS/ERG (165080) fusion transcript characteristic of the t(21;22)(q22;q21) translocation. Four and a half years later, the girl was found to have a second Ewing sarcoma, of the right proximal humerus, in which an EWS/FLI1 type 5 translocation was identified. Bielack et al. (2004) stated that this was the first report of such molecular heterogeneity in specimens of Ewing sarcoma from a single patient.

EWS/ATF1 FUSION GENE

Just as the fusion of the 5-prime portion of the EWS gene to the FLI1 gene results in Ewing sarcoma, fusion of the same part of the EWS gene to the ATF1 gene (123803) results in malignant melanoma of soft parts (MMSP) (Zucman et al., 1993).

In tumor tissue derived from a patient with angiomatoid fibrous histiocytoma (612160), Hallor et al. (2005) identified a t(12;22)(q13;q12) translocation. RT-PCR analysis detected an EWS/ATF1 fusion gene between exons 7 and 5, respectively, that functioned as a constitutive transcriptional activator.

In a tumor sample from a patient with angiomatoid fibrous histiocytoma, Antonescu et al. (2007) identified an EWSR1/ATF1 fusion gene linking exon 7 of EWSR1 to exon 5 of ATF1.

EWS/WT1 FUSION GENE

Desmoplastic small round cell tumor (DSRCT) is associated with a recurrent chromosomal translocation, t(11;22)(p13;q12). DSRCT is characterized by a predilection for young males, abdominal serosal involvement, poor prognosis, and a primitive histologic appearance. Because the recurrent chromosome translocation breakpoints in t(11;22)(p13;q12) associated with desmoplastic small round cell tumor are located cytogenetically in the regions of 2 tumor-associated genes, WT1 (607102) on chromosome 11 and EWS on chromosome 22, Gerald et al. (1995) investigated these genes as potential translocation partners in DSRCT and showed that they are consistently rearranged in genomic DNA isolated from tumor tissue. The breakpoints involved the intron between EWS exons 7 and 8 and the intron between WT1 exons 7 and 8. Chimeric transcripts corresponding to the fusion gene were detected in 4 of 6 cases studied. Analyses of these transcripts showed an in-frame fusion of RNA encoding the N-terminal domain of EWS to both alternatively spliced forms of the last 3 zinc fingers of the DNA-binding domain of WT1. Thus, DSRCT represents another tumor type associated with translocation of EWS; it is the first tumor associated with a consistent translocation involving WT1. The chimeric products were predicted to modulate transcription at WT1 target sites and contribute to the development of this unique tumor.

EWS/ETV1 FUSION GENE

Jeon et al. (1995) identified a variant type of Ewing sarcoma translocation, t(7;22)(p22;q12), that fused EWS to the ETV1 gene (600541).

Wang et al. (2007) reported 2 unrelated children with small round cell tumors harboring an EWS/ETV1 fusion gene resulting from the fusion of exon 7 to exon 10 or 11 in the 2 genes, respectively. Both were soft tissue tumors.

EWS/FEV FUSION GENE

Peter et al. (1997) described a t(2;22) translocation that fused the N-terminal transcription-activation domain of EWS to the ETS DNA-binding domain of FEV (607150) in a paraspinal tumor in a 2-year-old girl and in an extraosseous maxillary tumor in a 15-year-old boy. Sequence analysis indicated that exon 10 of EWS was linked in-frame to FEV.

Wang et al. (2007) identified a somatic EWS/FEV fusion gene in tissue derived from a 40-year-old man with a soft tissue tumor. The fusion joined exon 7 of EWS to exon 2 of FEV.

EWS/ZNF278 FUSION GENE

Mastrangelo et al. (2000) described a submicroscopic inversion of chromosome 22q in a small round cell sarcoma with a t(1;22)(p36.1;q12) translocation. The resultant chimeric transcript contained exon 8 of the EWS gene fused in-frame to exon 1 of the ZNF278 gene (605165), creating a protein with the transactivation domain of EWS fused to the zinc finger domain of ZNF278. Mastrangelo et al. (2000) found that the ZNF278 gene is located 2 Mb distal to EWS and is transcribed in the opposite orientation. Thus, they concluded that a paracentric inversion of 22q12 occurred to create the active EWS/ZNF278 fusion gene.

EWS/UQCRH FUSION GENE

Modena et al. (2003) characterized a translocation t(1;22)(p34;q12) that was associated with a paracentric inversion of chromosome 22q12 in a small round cell sarcoma. They had previously shown (Mastrangelo et al., 2000) that the inversion of chromosome 22q12 generated an EWS/ZSG (ZNF278; 605165) fusion gene. Modena et al. (2003) found that the t(1;22)(p34;q12) interrupted the UQCRH gene (613844), with the breakpoint in intron 3, and created fusion genes with both EWS on der(22) and ZSG on der(1). PCR analysis of tumor cDNA and genomic DNA detected 5-prime-UQCRH/EWS-3-prime, 5-prime-ZSG/UQCRH-3-prime, and 5-prime-EWS/ZSG-3-prime. Only 5-prime-EWS/ZSG-3-prime produced in-frame transcripts. In contrast, 5-prime-UQCRH/EWS-3-prime and 5-prime-ZSG/UQCRH-3-prime produced out-of-frame transcripts containing premature stop codons.

EWS/NR4A3 FUSION GENE

In tumor tissue derived from a patient with extraskeletal myxoid chondrosarcoma (EMC; 612237), Gill et al. (1995) demonstrated that a t(9;22)(q22-31;q11-12) translocation led to fusion of the EWS gene with a DNA segment from 9q22-q31. This particular t(9;22) was a recurrent cytogenetic finding in the myxoid variant of chondrosarcoma.

Panagopoulos et al. (2002) studied 18 cases of extraskeletal myxoid chondrosarcoma both cytogenetically and molecularly. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-q12, the sites of the NR4A3 (CHN) (600542) and EWS genes, respectively, and 3 with rearrangements involving 9q22 and 17q11, the sites of the NR4A3 and RBP56 genes (601574), respectively. An EWS/NR4A3 fusion transcript was found in 15 cases, and an RBP56/NR4A3 transcript in 3. The most frequent EWS/NR4A3 fusion transcript, present in 10 tumors, involved fusion of EWS exon 12 with NR4A3 exon 3; the second most common, present in 2 cases, was fusion of EWS exon 13 with NR4A3 exon 3.

Using a yeast functional complementation assay to identify possible functions of the EWS/NR4A3 (NOR1) fusion gene, Ohkura et al. (2002) determined that the EWS/NR4A3 fusion gene gains a novel activity affecting RNA. EWS/NR4A3 partially functioned as an snRNP in yeast and affected pre-mRNA splicing in mammalian cells. Mammalian cell studies showed that the EWS/NR4A3 fusion gene localized within the nucleus and showed characteristics similar to that of an RNA-binding protein. Overexpression of EWS/NR4A3 in mammalian cells resulted in increased usage of the distal 5-prime splice site of pre-mRNA splicing and that EWS/NR4A3 interacted with the U1C splicing protein. The findings suggested an oncogenic mechanism alternative to that of transcriptional control, and indicated that changes in pre-mRNA splicing may contribute to oncogenesis.

EWS/CREB1 Fusion Gene

In tumor tissue samples from 8 unrelated patients with angiomatoid fibrous histiocytoma (612160), Antonescu et al. (2007) identified an identical EWSR1/CREB1 (123810) fusion transcript with exon 7 of EWSR1 fused to exon 7 of CREB1. Antonescu et al. (2007) concluded that the EWSR1/CREB1 fusion gene is the most common genetic abnormality in this tumor type.

EWS/POU5F1 Fusion Gene

Yamaguchi et al. (2005) identified a t(6;22)(p21;q12) translocation in tumor tissue derived from an undifferentiated sarcoma from the pelvic bone of a 39-year-old woman. The translocation resulted in an EWS/POU5F1 chimeric gene composed of the N-terminal domain of EWS that functions as a transcriptional activation domain and the C-terminal DNA-binding domain of POU5F1. The authors suggested that the tumor may be variant of Ewing sarcoma.

EWS/SP3 Fusion Gene

Wang et al. (2007) identified an EWS/SP3 (601804) fusion gene in tumor tissue derived from a 16-year-old boy with an extraskeletal undifferentiated small round cell tumor. He had lesions in the extradural region, lung, and kidney. The EWS amino-terminal domain was fused to a zinc finger DNA-binding domain of SP3.

EWS/ETV4 Fusion Gene

Kaneko et al. (1996) identified a somatic t(17;22)(q12;q12) translocation in a MIC2 (CD99; 313470) antigen-positive undifferentiated sarcoma of infancy. On Southern blot analysis, EWS and E1AF (600711) cDNA probes hybridized to the same rearranged band, indicating that an EWS/E1AF fusion gene was formed in the tumor. Further Southern blot analysis showed that the breakpoint was in the region upstream to the ETS domain of the E1AF gene. Kaneko et al. (1996) concluded that the RNA binding domain of EWS may have been replaced by the DNA binding domain of E1AF in the EWS/E1AF fusion protein as in other fusion proteins previously characterized in various forms of Ewing sarcoma (612219).

Urano et al. (1996) identified a chimeric gene between the transactivation domain of EWS and E1AF in an extraskeletal Ewing sarcoma.

In the Ewing sarcoma tumors described by Kaneko et al. (1996) and Urano et al. (1996), Ishida et al. (1998) determined that the chimeric transcript represented an in-frame fusion between the 5-prime terminal region of EWSR1 and the 3-prime end of ETV4. The chimeric transcript could thus serve as a template for expression of a protein composed of the N-terminal portion of EWSR1 fused to the DNA-binding domain of ETV4. Long PCR and sequence analysis of genomic DNA revealed that either exon 8 or intron 7 of EWSR1 was fused to the same intron of ETV4 in both tumors. The 159-bp Alu-like sequence was repeated in the breakpoint region of the ETV4 gene, suggesting a mechanism of EWSR1/ETV4 gene fusion.


Genotype/Phenotype Correlations

In a review of 12 cases of unusual EWS fusion genes, Wang et al. (2007) concluded that tumors with EWS fusion to ETV1, ETV4, FEV, and SP3 tended to have strong predilection for extraskeletal primary sites. The tumors were often small round cell sarcomas of uncertain lineage.


Animal Model

Li et al. (2007) found that Ews +/- mice were indistinguishable from wildtype littermates and developed normally. Ews -/- pups were obtained at the expected mendelian ratio, but they were runted, and about 90% died prior to weaning, despite normal appearance of all major organs and normal suckling in most of the animals. Analysis of Ews -/- lymphocytes revealed a defect in pre-B cell development. During meiosis, Ews -/- spermatocytes were deficient in XY bivalent formation and showed reduced meiotic recombination, resulting in massive apoptosis and complete arrest in gamete maturation. Ews -/- fibroblasts showed premature cellular senescence, and Ews -/- animals were hypersensitive to ionizing radiation. Li et al. (2007) showed that Ews interacted with lamin A/C (LMNA; 150330), and loss of Ews resulted in reduced lamin A/C expression. Li et al. (2007) concluded that EWS has an essential role in pre-B cell development and meiosis and is involved in cellular senescence, and they proposed a role for EWS in DNA pairing and recombination/repair mechanisms.


REFERENCES

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Contributors:
Patricia A. Hartz - updated : 3/28/2011
Cassandra L. Kniffin - updated : 8/14/2008
Carol A. Bocchini - updated : 8/5/2008
Cassandra L. Kniffin - updated : 7/3/2008
Ada Hamosh - updated : 3/7/2008
Patricia A. Hartz - updated : 10/31/2007
Patricia A. Hartz - updated : 6/30/2005
Marla J. F. O'Neill - updated : 3/30/2004
Victor A. McKusick - updated : 1/14/2003
Patricia A. Hartz - updated : 8/15/2002
Paul J. Converse - updated : 7/14/2000
Victor A. McKusick - updated : 10/26/1999
Victor A. McKusick - updated : 9/3/1997
Victor A. McKusick - updated : 2/20/1997
Moyra Smith - updated : 12/13/1996

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
carol : 09/11/2023
alopez : 06/13/2022
carol : 01/26/2021
terry : 04/04/2013
terry : 6/7/2012
terry : 4/26/2011
terry : 4/26/2011
mgross : 3/28/2011
carol : 8/20/2008
ckniffin : 8/14/2008
carol : 8/12/2008
carol : 8/5/2008
wwang : 7/8/2008
ckniffin : 7/3/2008
alopez : 3/20/2008
alopez : 3/20/2008
terry : 3/7/2008
mgross : 11/1/2007
terry : 10/31/2007
wwang : 6/30/2005
carol : 4/16/2004
tkritzer : 4/1/2004
terry : 3/30/2004
joanna : 3/16/2004
joanna : 11/6/2003
joanna : 9/23/2003
carol : 5/20/2003
carol : 5/20/2003
carol : 5/20/2003
carol : 1/21/2003
tkritzer : 1/16/2003
terry : 1/14/2003
ckniffin : 10/3/2002
ckniffin : 8/26/2002
mgross : 8/23/2002
mgross : 8/15/2002
mgross : 7/14/2000
mcapotos : 2/7/2000
carol : 10/27/1999
terry : 10/26/1999
carol : 8/25/1998
terry : 7/24/1998
terry : 5/29/1998
terry : 9/8/1997
terry : 9/3/1997
terry : 8/12/1997
mark : 2/20/1997
terry : 2/13/1997
mark : 12/13/1996
jenny : 12/9/1996
mark : 12/9/1996
mark : 5/21/1995
carol : 3/3/1995
mimadm : 9/24/1994
carol : 9/10/1993
carol : 7/6/1993
carol : 1/11/1993