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ewsr1

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Official Full Name
EWS RNA-binding protein 1
Background
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.
Synonyms
EWSR1; Ewing sarcoma breakpoint region 1; RNA-binding protein EWS; EWS; Ewings sarcoma EWS-Fli1 (type 1) oncogene; bK984G1.4; EWS RNA-binding protein 1

Ewing sarcoma breakpoint region 1 gene (EWSR1) is a member of the TET family, which includes three molecules, FUS/TLS, EWSR1 and TAF15, all of which belong to RNA-binding proteins. TET family proteins are expressed in various tissues. Because they possess a nuclear localization sequence, they are mainly located in the nucleus, but may also be translocated into the cytosol under stress or pathological conditions. Both TET family proteins have a transcriptional activation domain and an RNA binding domain and contain multiple conserved structures such as serine-tyrosine-glycine-glutamine domain (SYGQ), RNA recognition motif (RRM), zinc finger motif, arginine-glycine-glycine rich region (RGG) and the like. In addition to direct binding to RNA, TET family proteins can also bind to DNA, and can also act as transcriptional cofactors to directly bind to transcription factors, including biological processes including gene expression regulation, mRNA splicing editing, signal pathway regulation, and DNA repair.

The researchers identified another translocation of the EWSR1 gene in soft tissue malignant melanoma, which consists of the N-terminal domain of EWSR1 and the bZIP domain of the transcription factor ATF-1. In addition, the EWSR1 gene can also form tumor-specific fusion protein transcription factors with a variety of transcription factors such as ERG, NR4A3, and CHOP. The common feature of these EWSR1 fusion proteins is that the N-terminal transcriptional activation domain of EWSR1 is fused to the DNA-binding domain of the C-terminus of a transcription factor, thereby enabling DNA binding activity and transcriptional regulation. These fusion proteins have a strict relationship with tumor types and are thought to play a key role in the pathogenesis and formation of tumors.

However, in a tumor expressing an EWSR1 fusion protein, only one allele translocation occurs, and the other allele still expresses EWSR1. This suggests that in addition to chromosomal ectopic, EWSR1 may also play a role in tumorigenesis through other mechanisms.

EWSR1 Gene Break and Tumor

Ewing's sarcoma is the second most common osteosarcoma in children and young adults, including Ewing's sarcoma/primary neuroectodermal tumors. It also includes primitive neuroectodermal tumors, Aslan tumors, olfactory neuroblastoma, malignant interstitial tumors and extra-orbital Ewing sarcoma, a group of blues chroma cell tumor with the same histological and molecular characteristics present in bone and soft tissue. Most cases occur in the soft tissues of the vertebrae and proximal extremities, and can also occur in the internal organs such as the kidney, pancreas, and meninges. Ewing sarcoma can occur at any age, and more than 90% of Ewing's sarcoma undergo translocation of EWSR1 and ETS family genes FLI1 and ERG. The fusion proteins formed by these translocations can target genes involved in cell growth, proliferation, senescence, and tumorigenesis, thereby altering the fate of cells, leading to abnormal proliferation and producing different types of tumors. Therefore, research on the function of EWSR1 mainly focuses on the process of forming fusion proteins with various transcription factor translocations to participate in the development of malignant tumors. The sequence encoding the RNA-binding domain of the EWSR1 gene and the sequence encoding the DNA-binding domain of the FLI1 gene translocate, thereby changing the open reading frame of the EWSR1 gene on chromosome 22.

EWSR1 Figure 1. The influence of EWSR1-ETS fusion protein at the transcriptome level. (Sand, et al. 2015)

Approximately 85% of Ewing's sarcoma cytogenetics have at(11;22)(q24;q12) translocation leading to the EWSR1-FLI1 fusion gene, which plays an important transcription factor in Ewing's sarcoma. The prognosis of patients with Ewing sarcoma is related to the clinical stage, location and tumor size of the tumor, as well as TP53 status, CDKN2A deletion, telomerase expression, and chromosome 1q acquisition. The type of EWSR1-ETS gene fusion is less related to the prognosis of patients with Ewing's sarcoma. However, it should be noted that the EWSR1 gene break can also occur in the following soft tissue tumors. In addition, EWSR1 gene breaks can also occur in non-soft tissue tumors, including acute myeloid leukemia, granulocyte sarcoma, and acute B lymphoblastic leukemia. Cao et al. reported that 1 case of parental plasmacytoid dendritic cell tumor also had EWSR1 gene break. Recently, it has been reported in the literature that EWSR1 gene breaks are also common in papillary thyroid carcinoma and thyroid carcinoma with Ewing sarcoma family tumor components.

A characteristic cytogenetic abnormality of mucin-like liposarcoma is that the t(12;16) (q13;p11) translocation results in a FUS-DDIT3 (CHOP) fusion gene, and more than 95% of mucinous liposarcomas have the fusion gene. The fusion gene is a highly sensitive and specific molecular marker of mucin-like liposarcoma, while other tumors of similar morphology, including mucosal hyperdifferentiation/dedifferentiated liposarcoma and mucinous fibrosarcoma, lack the fusion gene. At present, there is insufficient evidence to support the existence of mixed mucinous liposarcoma and dedifferentiated liposarcoma. A few t(12;22) (q13;q12) translocations result in the EWSR1-DDIT3 fusion gene.

Gastrointestinal malignant neuroectodermal tumor: This tumor was named early in the "gastrointestinal clear cell sarcoma", "gastrointestinal clear cell sarcomatoid tumor" and the like. The study reported 16 cases of this tumor, which is considered to be an independent tumor with neuroectodermal differentiation characteristics and lack of melanin phenotype, and was named "gastrointestinal malignant neuroectodermal tumor". Most gastrointestinal malignant neuroectodermal tumors have an EWSR1-ATF1 or EWSR1-CREB1 fusion gene.

References:

  1. Sand, L. G. L., Karoly, S., & Hogendoorn, P. C. W. (2015). Sequencing overview of ewing sarcoma: a journey across genomic, epigenomic and transcriptomic landscapes. International Journal of Molecular Sciences,16(7), 16176-16215.
  2. Cantile, Monica, Marra, Laura, Franco, & Renato, et al. (2013). Molecular detection and targeting of ewsr1 fusion transcripts in soft;tissue tumors. Medical Oncology, 30(1), 412.
  3. Rekhi, B., Vogel, U., Basak, R., Desai, S. B., & Jambhekar, N. A. (2014). Clinicopathological and molecular spectrum of ewing sarcomas/pnets, including validation of ewsr1 rearrangement by conventional and array fish technique in certain cases. Pathology & Oncology Research, 20(3), 503-516.
  4. Cao, Q., Liu, F., Niu, G., Xue, L., & Han, A. (2014). Blastic plasmacytoid dendritic cell neoplasm with ewsr1 gene rearrangement. Journal of Clinical Pathology, 67(1), 90-2.
  5. Oliveira, G., Polónia, A., Cameselle-Teijeiro, J. M., Leitão, D., Sapia, S., & Sobrinho-Simões, M., et al. (2017). Ewsr1 rearrangement is a frequent event in papillary thyroid carcinoma and in carcinoma of the thyroid with ewing family tumor elements (cefte). Virchows Archiv, 470(5), 1-9.