Primitive round- or spindle-cell EWSR1-negative undifferentiated sarcomas harboring CIC-DUX4 gene fusion are the most common form of Ewing-like sarcomas.
The current version now includes PEComatous tumors, myoepithelial tumors, and pulmonary myxoid sarcomas with <i>EWSR1-CREB1</i> translocation as new disease entities.
EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies.
EWSR1-PATZ1 fusion positive spindle and round cell sarcomas show abundant intratumoral fibrosis and polyphenotypic differentiation, thus mimicking a range of tumors including desmoplastic small round cell tumor.
In the new review all the tumors were re-classified as, ES (n=16), Ewing-like tumor with EWSR1 rearrangement and amplification and possible EWSR1-NFATC2 gene fusion (n=1), CIC-rearranged sarcomas or undifferentiated sarcoma, most consistent with CIC-rearranged sarcoma (n=7), sarcoma with BCOR-alteration or undifferentiated sarcoma, consistent with BCOR-associated sarcoma (n=3), neuroblastoma (n=2), unclassifiable neoplasm with neuroblastic differentiation (n=1), malignant rhabdoid tumor (n=2), lymphoblastic lymphoma (n=1), clear cell sarcoma of the gastrointestinal tract (n=1), small cell carcinoma (n=1), sclerosing rhabdomyosarcoma (n=1), desmoplastic small round cell tumor (n=1), malignant peripheral sheath nerve tumor (n=1), poorly-differentiated synovial sarcoma (n=1), Possible gastrointestinal stromal tumor/GIST with predominant round cells (n=1) and possible SMARCA4-deficient-sarcoma (n=1).
We retrospectively reviewed all cases of histologically- and molecularly-confirmed CCSLTGT with EWSR1-CREB1 or EWSR1-ATF1 fusions at our tertiary sarcoma center, between 2009 and 2016.
We analysed the spectrum of EWSR1-rearranged soft tissue neoplasms at our tertiary sarcoma centre, by assessing ancillary molecular diagnostic modalities identifying EWSR1-rearranged tumours and reviewing the results in light of our current knowledge of these and other Ewing sarcoma-like neoplasms.
Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins.
Recurrent gene fusions involving EWSR1 with members of the cAMP response element binding protein (CREB) family (ATF1 and CREB1) have been reported in a diverse group of tumors including angiomatoid fibrous histiocytoma (AFH), soft tissue and gastrointestinal clear cell sarcoma, primary pulmonary myxoid sarcoma, and hyalinizing clear cell carcinoma of salivary gland.
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas.
A histologic comparison of the CIC-rearranged sarcomas with 20 EWSR1-rearranged Ewing sarcomas showed significantly higher degrees of lobulation, nuclear pleomorphism, the prominence of the nucleoli, spindle cell elements, and myxoid changes in the CIC-rearranged sarcomas.
This chapter will focus on the unique genetic and epigenetic changes which characterize these cancers, with an emphasis on translocation-associated sarcomas involving primary gene fusions with the RNA chaperone protein EWSR1.
Study of alternative molecular alterations in EWSR1-negative undifferentiated small round cell sarcomas is clinically relevant, since CIC-DUX4 sarcomas seem to be a very aggressive subset with poor response to the presently used therapeutic regimens.
Gene rearrangements involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene are seen in a broad range of sarcomas and some nonmesenchymal neoplasms.
Among the genes that can be rearranged, the EWSR1 gene has been identified as a partner in a wide variety of clinically and pathologically diverse sarcomas as well as some non-mesenchymal tumours.
The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas.
Although we acknowledge that the present molecular classification of soft tissue tumours is much more complex than two decades ago, when EWSR1 gene rearrangements had been described as the hallmark of Ewing sarcoma, we make the strong argument that with very few exceptions, the prevalence of fusion transcripts in most sarcomas is such that they come to define these entities and can be used as highly specific molecular diagnostic markers in the right clinical and pathological context.