Molecular detection and targeting of EWSR1 fusion transcripts in soft tissue tumors

Abstract

Soft tissue tumors are a heterogeneous group of tumors, traditionally classified according to morphology and histogenesis. Molecular classification divides sarcomas into two main categories: (a) sarcomas with specific genetic alterations and (b) sarcomas showing multiple complex karyotypic abnormalities without any specific pattern. Most chromosomal alterations are represented by translocations which are increasingly detected. The identification of fusion transcripts, in fact, not only support the diagnosis but also provides the basis for the development of new therapeutic strategies aimed at blocking aberrant activity of the chimeric proteins. One of the genes most susceptible to breakage/translocation in soft tissue tumors is represented by Ewing sarcoma breakpoint region 1 (EWSR1). This gene has a large number of fusion partners, mainly associated with the pathogenesis of Ewing’s sarcoma but with other soft tissue tumors too. In this review, we illustrate the characteristics of this gene/protein, both in normal cellular physiology and in carcinogenesis. We describe the different fusion partners of EWSR1, the molecular pathways in which is involved and the main molecular biology techniques for the identification of fusion transcripts and for their inhibition.

Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra

“…For example, the BCR-ABL1 fusion protein is observed in 2% of childhood acute lymphoid leukemia (ALL) but up to 25% of adult ALL cases (4). Certain tumors that occur primarily in children and young adults are marked by characteristic alterations, such as BRAF alterations in low-grade gliomas, EWSR1 fusions in Ewing sarcoma, and ALK alterations in neuroblastoma (5)(6)(7). In some cases, the identification of genomic alterations has guided targeted therapy selection.…”

Unusual Clinical Presentation of Gastrointestinal Clear Cell Sarcoma

“…1b, 4b) is somewhat more compatible with CCS than ES diagnosis [3]. Finally, this case exemplifies that the use of anonymous assays, such as break-apart FISH EWSR1 testing, may lead to erroneous results, so the identification of the translocation gene partners is indeed important for proper sarcoma management [10,11,12]. A series of similar tumors, which were characterized by gastrointestinal location, sarcoma-like histology, absence of melanocytic markers, distinct ultrastructural features and presence of EWSR1 translocations (including EWSR1-ATF1 and EWSR1-CREB1 fusions), has recently been described by Stockman et al [13]; they suggest to designate this tumor entity as malignant gastrointestinal neuroectodermal tumors.…”

Simultaneous deletion of 3′ETV6 and 5′EWSR1 genes in blastic plasmacytoid dendritic cell neoplasm: case report and literature review

“…EWSR1 rearrangement has been reported mostly in soft tissue tumors [42–44], also rarely in hematologic malignancies [37, 45, 46], but only in one BPDCN case previously [37]. The EWSR1 gene has a large number of fusion partners, including members of the ets family, such as FLI1 , ERG and ETV1 but not ETV6 [42–44]. As mentioned above, according to the locations of the remaining 5′ETV6 and 3′EWSR1 , an ETV6/EWSR1 fusion can be excluded in this case.…”