EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

Abstract

EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.

EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity

“…EWSR1 plays biological roles in epigenetic regulation of gene expression, RNA processing, signal transduction, and microRNA regulation. [43][44][45] Yin Yang 1 (YY1) is a ubiquitous transcription factor that plays a fundamental role in normal biological processes including embryogenesis, cellular differentiation, and proliferation. When YY1 is overexpressed or activated, it is associated with unmitigated cellular proliferation, apoptotic resistance, tumorigenesis and metastasis.…”

“…EWSR1 is ubiquitously expressed in most cell types and belongs to the FET family of RNA‐binding proteins, which also include Fused in Sarcoma (FUS) and TATA‐box binding protein Associated Factor 15 (TAF15). EWSR1 plays biological roles in epigenetic regulation of gene expression, RNA processing, signal transduction, and microRNA regulation 43–45 . Yin Yang 1 (YY1) is a ubiquitous transcription factor that plays a fundamental role in normal biological processes including embryogenesis, cellular differentiation, and proliferation.…”

A case report of malignant neuroectodermal tumor of the gastrointestinal tract without common gene fusion in a soft tissue tumor

“…A molecular genetic study of most GNETs has found EWSR1 gene rearrangements, usually fused with ATF1 or CREB1 (4). EWSR1 has a propensity for fusing (as the 5' partner) with a host of different genes, with its product being a member of the FET (FUS/EWSR1/TAF15) family of transcription factors (7). More than 70% of GNETs show EWSR1-ATF1 fusions, with 20-30% of cases showing EWSR1-CREB1 fusions.…”

Functional analysis across model systems implicates ribosomal proteins in growth and proliferation defects associated with hypoplastic left heart syndrome

“…In contrast to hPSC-CMs, siEWSR1 did not affect the number of OCT4+ cells (Figure 6F, G), which suggests that EWSR1 is able to regulate proliferation CM-specifically. EWSR1 is an RNA/DNA binding protein that regulates transcription and RNA splicing and plays a major role as oncogenic driver when fused to ETS transcription factors [60]. In a next step, we tested if EWSR1 regulates CM proliferation by modulating the p53 pathway.…”