The Ewing sarcoma breakpoint region gene EWSR is a
The Ewing sarcoma breakpoint region 1 gene (EWSR1) is a partner in a large, diverse range of mesenchymal (and some nonmesenchymal) tumors (Tables 1 and 2). As the 5′ partner, EWSR1 is able to fuse with an array of genes. These fusions can generate genetically different but phenotypically identical neoplasms. Alternatively, EWSR1 can fuse with the same gene in clinically and histologically different tumors. Mesenchymal neoplasms harboring EWSR1 gene rearrangements include ES, myxoid liposarcoma (MLPS),5, 6, 7, 8, 9 clear cell sarcoma of soft tissue (CCS), and clear cell sarcoma-like tumors of gastrointestinal tract (CCSLTGT),10, 11, 12 angiomatoid fibrous histiocytoma (AFH),13, 14, 15, 16 desmoplastic small round cell tumor (DSRCT),17, 18, 19 extraskeletal myxoid chondrosarcoma (EMC),20, 21, 22, 23, 24, 25, 26, 27 primary pulmonary myxoid sarcoma (PPMS), myoepithelial tumors of skin, soft tissue and bone,29, 30 some sclerosing epithelioid fibrosarcomas (SEF), and low-grade fibromyxoid sarcomas (LGFMS) and newly described myxoid neoplasms harboring EWSR1-CREM fusions, which predominate in intracranial sites of young patients. This article reviews the spectrum of mesenchymal neoplasms that harbor EWSR1 gene rearrangements.
The EWSR1 gene is a member of the TET (translocated in liposarcoma [TLS]/fused in sarcoma [FUS], EWSR1, TATA-binding protein-associated factor 15 [TAF15]) family, a group of TG4-155 involved in several translocation-associated sarcomas.35, 36, 37, 38, 39 EWSR1, sited between base-pairs 29,663,998 and 29,696,515 on chromosome 22q12, was first noted to be rearranged in ES and encodes a multifunctional protein involved in a variety of cellular mechanisms, including gene expression, meiotic and mitotic cell division, cell signaling, DNA repair, and cellular aging.38, 41, 42 EWSR1 has a 17-exon coding sequence,43, 44 which encodes a 656-amino-acid nuclear protein, which includes a carboxy-terminus 87-amino-acid RNA-binding domain (exons 11–13) involved in protein-RNA binding, transcription, and RNA metabolism.43, 46 EWSR1 and FUS are highly homologous and can variably serve as alternative binding partners in several translocation-associated tumors, including AFH, MLPS, LGFMS, and SEF. Other TET family gene members may function as alternatives to EWSR1 in genetic rearrangements, such as TAF15, which can act as a partner in some examples of EMC. EWSR1 fusion sites vary for different neoplasms; exon 7 is the most frequent site in ES,49, 50 in EWSR1-WT1 of DSRCT, in EWSR1-DDIT3 of MLPS,5, 6, 51, 52 and in EWSR1-CREB1 of PPMS. However, in CCS, the most frequent EWSR1 fusion site is exon 8 and for EWSR1-NR4A3 in EMC it is exon 12.
The ATF1 gene encodes the cyclic AMP-dependent transcription factor ATF1. This gene is a member of the cyclic-AMP response element binding protein (CREB)-ATF transcription factor family, which binds to cyclic adenosine monophosphate (cAMP)-inducible promoters. CREB proteins are related in functional terms to ATF, with CREB1 serving as an alternative gene to ATF1 in AFH and CCS. EWSR1-ATF1 and/or EWSR1-CREB1 gene fusions are characteristically associated with 5 clinically and pathologically different tumors: AFH, CCS (of tendons and aponeuroses), CCSLTGT, PPMS, and hyalinizing clear cell carcinoma (HCCC) of the salivary gland. EWSR1-ATF1 fusion has also been reported in a soft tissue myoepithelial tumor as well as in a parotid gland angiosarcoma. The soft tissue neoplasms of this group of tumors do not resemble any normal cellular counterpart. CCS and CCSLTGT show variable melanocytic differentiation, whereas AFH can variably show myoid features and PPMS does not show a detectable lineage. Identical gene fusions might generate phenotypically different neoplasms because of the influences of different anatomic sites on similar progenitor cells, or because they occur in different progenitor cells (possibly mesenchymal stem cells), which activate specific sets of transcription factors. EWSR1-ATF1 fusion transcripts are characteristic of HCCC, a low-grade carcinoma typically occurring in intraoral minor salivary glands in adult women150, 151, 152, 153 and its odontogenic counterpart clear cell odontogenic carcinoma (CCOC); these tumors are composed of infiltrative nests of uniform cells with granular to clear cytoplasm in myxohyaline stroma and express cytokeratins and EMA, but lack myoepithelial differentiation and are negative for actin, calponin, and S100 protein.150, 151, 154, 155 EWSR1-CREB1 is now also described in CCOC, and these genetics demonstrate that this fusion can generate neoplasms with epithelial differentiation. Salivary glandular carcinomas, which can mimic HCCC such as epithelial-myoepithelial carcinoma, lack EWSR1 rearrangements.