<i>EWSR1-CREB1</i> and <i>EWSR1-ATF1</i> Fusion Genes in Angiomatoid Fibrous Histiocytoma

Rossi, Sabrina; Szuhai, Károly; IJszenga, Marije; Tanke, Hans J.; Zanatta, Lucia; Sciot, Raf; Fletcher, Christopher D.�M.; Tos, Angelo Paolo Dei; Hogendoorn, Pancras C.W.

doi:10.1158/1078-0432.ccr-07-1744

Cited by 197 publications

(116 citation statements)

References 22 publications

(39 reference statements)

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“…Interestingly, EWSR1-ATF1 fusions were originally described in conventional clear cell sarcomas (of tendons and aponeurosis) [46] and have recently also been encountered in angiomatoid fibrous histiocytomas [47] as well as in a few cases of soft tissue myoepithelial tumors [48]. Taken together, these observations provide evidence for a unifying concept of salivary gland and soft tissue tumors with clear cell morphology.…”

Section: Ewsr1-atf1 Gene Fusion In Low-grade Hyalinizing Clear Cell Cmentioning

confidence: 67%

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

Stenman

2013

Head and Neck Pathol

173

167

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Salivary gland tumors constitute a heterogeneous group of uncommon diseases that pose significant diagnostic and therapeutic challenges. However, the recent discovery of a translocation-generated gene fusion network in salivary gland carcinomas as well in benign salivary gland tumors opens up new avenues for improved diagnosis, prognostication, and development of specific targeted therapies. The gene fusions encode novel fusion oncoproteins or ectopically expressed normal or truncated oncoproteins. The major targets of the translocations are transcriptional coactivators, tyrosine kinase receptors, and transcription factors involved in growth factor signaling and cell cycle regulation. Notably, several of these targets or pathways activated by these targets are druggable. Examples of clinically significant gene fusions in salivary gland cancers are the MYB-NFIB fusion specific for adenoid cystic carcinoma, the CRTC1-MAML2 fusion typical of low/intermediate-grade mucoepidermoid carcinoma, and the recently identified ETV6-NTRK3 fusion in mammary analogue secretory carcinoma. Similarly, gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign pleomorphic adenomas. Continued studies of the molecular consequences of these fusion oncoproteins and their down-stream targets will ultimately lead to the identification of novel driver genes in salivary gland neoplasms and will also form the basis for the development of new therapeutic strategies for salivary gland cancers and, perhaps, other neoplasms.

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Section: Ewsr1-atf1 Gene Fusion In Low-grade Hyalinizing Clear Cell Cmentioning

confidence: 67%

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

Stenman

2013

Head and Neck Pathol

173

167

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“…25 Both angiomatoid fibrous histiocytoma and clear cell sarcoma harbor the same two translocation variants, EWSR1-ATF1 t(12;22)(q13;q12) and EWSR1-CREB1 t(2;22)(q34;q12), yet both are phenotypically distinct from each other with distinctly different clinical courses. [27][28][29][30] More recently, recurrent EWSR1-CREB1 translocations have also been identified in hyalinizing clear cell carcinoma of the salivary gland. 26 Other examples include involvement of ALK-TPM3 in inflammatory myofibroblastic tumor and anaplastic large cell lymphomas, and ETV6-NTRK in infantile fibrosarcoma, secretory breast carcinomas, and acute myeloid leukemia.…”

Section: Resultsmentioning

confidence: 99%

FUS rearrangements are rare in ‘pure' sclerosing epithelioid fibrosarcoma

et al. 2012

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Several recent reports have described low-grade fibromyxoid sarcoma with sclerosing epithelioid fibrosarcoma-like areas. We evaluated cases of pure sclerosing epithelioid fibrosarcoma lacking areas of low-grade fibromyxoid sarcoma for FUS rearrangement to determine whether this entity could be related to low-grade fibromyxoid sarcoma. Available formalin-fixed paraffin-embedded tissue of 27 sclerosing epithelioid fibrosarcoma from 25 patients was retrieved and tabulated with clinical information. Unstained slides from formalin-fixed paraffin-embedded blocks were prepared and fluorescence in-situ hybridization was performed using a commercial FUS break-apart probe. The median patient age at presentation was 50 (range, 14-78) years, with 14 males and 10 females. Sclerosing epithelioid fibrosarcoma most commonly involved the extremities (n ¼ 8) or chest (n ¼ 6). Sixteen patients had a median follow-up of 17 (range, 1-99) months; seven were alive and well at 12 (range, 5-30) months; three alive with disease at 28 (range, 9-99) months; five dead of disease at a median of 22 (range, 1-36) months and one was dead of unknown causes. Twelve patients were known to have metastases; the most common site was lung (n ¼ 7), followed by bone (n ¼ 3), lymph nodes (n ¼ 2) and peritoneum (n ¼ 1). Only 2 of 22 (9%) analyzable cases of sclerosing epithelioid fibrosarcoma showed rearrangement in the FUS locus by fluorescence in-situ hybridization. Although cytogenetically confirmed lowgrade fibromyxoid sarcoma can have sclerosing epithelioid fibrosarcoma-like areas, FUS rearrangement, which is characteristic of low-grade fibromyxoid sarcoma, appears to be relatively rare in pure sclerosing epithelioid fibrosarcoma.

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“…51 FUS can serve as an alternative to EWSR1 in other sarcomas (eg, FUS-ERG in Ewing sarcoma 51 and acute myeloid leukemia 52 and FUS-DDIT3 in myxoid liposarcoma), 53,54 and EWSR1 and FUS appear to serve as alternative 5 0 partners with the ATF1 gene. 47 EWSR1-CREB1 is the most frequently described gene fusion to date, having been described in more than 90% of cases, 43,44 although EWSR1-ATF1 appears to be more common in AFH occurring in extrasomatic soft tissue sites. 6 FUS-ATF1 has been described least commonly.…”

Section: Histopathologymentioning

confidence: 99%

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

Thway

Fisher

2015

Archives of Pathology &Amp; Laboratory Medicine

117

134

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Context.-Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features.Objective.-To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions.Data Sources.-Review of published literature, including case series, case reports, and review articles, in online medical databases.Conclusions.-The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow-up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms.

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EWSR1-CREB1 and EWSR1-ATF1 Fusion Genes in Angiomatoid Fibrous Histiocytoma

Cited by 197 publications

References 22 publications

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

Fusion Oncogenes in Salivary Gland Tumors: Molecular and Clinical Consequences

FUS rearrangements are rare in ‘pure' sclerosing epithelioid fibrosarcoma

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

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