EWSR1 fusions: Ewing sarcoma and beyond

Abstract

received a BA at Williams College in Williamstown, Massachusetts, and an MD at the University of Virginia in Charlottesville, Virginia, where she also completed her Anatomic and Clinical Pathology residency. She did her fellowship training in soft-tissue pathology and cytopathology at Brigham and Women's Hospital (BWH) in Boston, Massachusetts, and joined the BWH faculty in 2012 and is currently an Assistant Professor at Harvard Medical School. She is active in the head and neck, soft-tissue, and cytopathology services at BWH and Dana-Farber Cancer Institute, with research interests in the clinicopathologic characterization of soft-tissue and head and neck neoplasms and the development of diagnostic biomarkers in surgical pathology and cytopathology.Over the past several decades, molecular genetics has revolutionized the field of soft-tissue pathology and expanded our diagnostic abilities as cytopathologists. Many soft-tissue neoplasms are now known to harbor defining molecular genetic alterations, and at least one-third of tumor types have recurrent chromosomal translocations. Ewing sarcoma, the prototypical "small round blue cell tumor," was the first sarcoma recognized to harbor a recurrent cytogenetic abnormality, most commonly the translocation t(11;22) (q24;q12). 1 This translocation results in a fusion gene involving the Ewing sarcoma breakpoint region 1 gene (EWSR1) and the friend leukemia virus integration 1 gene (FLI1). 2,3 Since discovery of the EWSR1-FLI1 fusion in Ewing sarcoma, numerous studies have led to insights into the molecular mechanisms of tumorigenesis in Ewing sarcoma as well as the continued discovery of defining molecular alterations that have affected soft-tissue tumor classification, although much remains to be elucidated.The EWSR1 gene, encoded on chromosome 22q12, is a member of the TET family, a highly conserved group of multifunctional, RNA-binding proteins. 4 EWSR1 has a 17-exon coding sequence, which encodes a 656-aminoacid protein that is highly conserved among TET family genes (including FUS and TAF15). Roles for EWSR1 have been implicated in transcription, DNA repair mechanisms, meiotic and mitotic cell division, and cellular aging. The N-terminus (exons 1-7) mediates transcriptional activation through degenerate repeats of the SYGQ motif, whereas the C-terminus contains an 87-amino-acid RNA-recognition motif encoded by exons 11 through 13. 4 Although variable, the majority (80%) of the breakpoints in EWSR1 occur in intron 7 or 8, resulting in fusion of the EWSR1 N-terminus to heterologous DNA-binding domains of its partners. 5,6 EWSR1-FLI1 fusions have long been considered to result from a balanced translocation (ie, transposition of chromosomal material without loss of genetic material); however, recent studies have demonstrated that these fusions can arise in the context of chromoplexy in approximately 40% of Ewing sarcomas, which are associated with a poorer prognosis. 7 Chromoplexy refers to the disruption of multiple, geographically distant genomic regions through multip...

Identification of Hub Genes Associated With the Development of Stomach Adenocarcinoma by Integrated Bioinformatics Analysis

“…EWSR1 is a polyfunctional protein that regulates cell function and aging by a variety of pathways, and is associated with the occurrence of mesenchymal tumors, multiple myeloma, Ewing’s sarcoma, and other tumors ( 11 – 13 ). PCMT1 is an unfavorable prognostic biomarker that participates in cell migration and invasion by regulating EMT-related genes ( 14 ).…”

Locally advanced malignant solitary fibrous tumour successfully treated with conversion chemotherapy, operation and postoperative radiotherapy: a case report

“…FISH showed no gene translocation, either in EWSR1, SS18 or FUS , whose gene fusions are traditionally regarded as pathognomonic for diagnosis of Ewing sarcoma, synovial sarcoma and myxoid/round cell liposarcoma, respectively. 20–22…”

“…FISH showed no gene translocation, either in EWSR1, SS18 or FUS, whose gene fusions are traditionally regarded as pathognomonic for diagnosis of Ewing sarcoma, synovial sarcoma and myxoid/round cell liposarcoma, respectively. [20][21][22] The best treatment option for MSFT is surgical resection with enough margin, and this is also the most important key factor in survival. 12 There is no standard treatment for locally advanced or metastasised SFT, including preoperative or postoperative treatment.…”

Fine Needle Aspiration Cytology of Malignant Digestive System Gastrointestinal Neuroectodermal Tumor in a Lymph Node Metastasis from a Previously Diagnosed Liver Primary: A Case Report and Review of Literature

“…The behavior of GNET does not correlate with the fusion type and is uniformly aggressive 9 . The EWSR1 rearrangements are not unique to GNET and can be seen in other diagnostic entities like Ewing sarcoma, hyalinizing clear cell carcinoma of salivary gland, myoepithelial tumors, extraskeletal myxoid chondrosarcoma, myxoid liposarcoma, angiomatoid fibrous histiocytoma, and desmoplastic round cell tumor, among others 14‐17 …”