scholarly journals Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors

Science ◽  
2018 ◽  
Vol 361 (6405) ◽  
pp. eaam8419 ◽  
Author(s):  
Nathaniel D. Anderson ◽  
Richard de Borja ◽  
Matthew D. Young ◽  
Fabio Fuligni ◽  
Andrej Rosic ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Ewing Sarcoma ◽  
Rna Binding ◽  
Fusion Gene ◽  
Soft Tissue Tumors ◽  
Gene Fusions ◽  
Gene Encoding ◽  
Reciprocal Translocations ◽  
Whole Genomes ◽  
Genomic Regions

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

scholarly journals FOXO1 gene involvement in a non-rhabdomyosarcomatous neoplasm

2021 ◽  
Author(s):  
Simon Haefliger ◽  
Muriel Genevay ◽  
Michel Bihl ◽  
Romina Marone ◽  
Daniel Baumhoer ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Soft Tissue ◽  
Genetic Heterogeneity ◽  
Gene Fusion ◽  
Fusion Gene ◽  
Soft Tissue Tumors ◽  
Gene Fusions ◽  
Mesenchymal Tumors ◽  
Myoepithelial Differentiation ◽  
Foxo1 Gene

AbstractMyoepithelial neoplasms of soft tissue are rare tumors with clinical, morphological, immunohistochemical, and genetic heterogeneity. The morphological spectrum of these tumors is broad, and the diagnosis often requires immunostaining to confirm myoepithelial differentiation. Rarely, tumors show a morphology that is typical for myoepithelial neoplasms, while the immunophenotype fails to confirm myoepithelial differentiation. For such lesions, the term “myoepithelioma-like” tumor was introduced. Recently, two cases of myoepithelioma-like tumors of the hands and one case of the foot were described with previously never reported OGT-FOXO gene fusions. Here, we report a 50-year-old woman, with a myoepithelial-like tumor localized in the soft tissue of the forearm and carrying a OGT-FOXO1 fusion gene. Our findings extend the spectrum of mesenchymal tumors involving members of the FOXO family of transcription factors and point to the existence of a family of soft tissue tumors that carry the gene fusion of the OGT-FOXO family.

Peripheral primitive neuroectodermal tumors in adults: documentation by molecular analysis.

1998 ◽  
Vol 16 (3) ◽  
pp. 1150-1157 ◽  
Author(s):  
E R Lawlor ◽  
J A Mathers ◽  
T Bainbridge ◽  
D E Horsman ◽  
A Kawai ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Molecular Analysis ◽  
Fusion Gene ◽  
Molecular Diagnostic ◽  
Gene Fusions ◽  
Primitive Neuroectodermal Tumors ◽  
Pathologic Features ◽  
Neuroectodermal Tumors ◽  
Objective Evidence ◽  
Peripheral Primitive Neuroectodermal Tumors

PURPOSE The Ewing tumor (ET) family of peripheral primitive neuroectodermal tumors (pPNETs) are primitive small round-cell tumors (SRCTs) of the bone and soft tissue that occur predominantly in children and adolescents. However, pPNETs only rarely enter the differential diagnosis of bone and soft tissue SRCTs in adults. Recently, gene fusions between the EWS gene and different members of the ETS transcription factor family have been shown to occur in virtually all pPNETs and thus constitute a pathognomonic marker for this tumor subclass. The aim of the present study was to document EWS/ETS fusion gene expression in suspected pPNETs of adults as objective evidence for the existence of this tumor family in older patients. PATIENTS AND METHODS The three contributing molecular diagnostic laboratories retrospectively compiled a cohort of all SRCT cases in which EWS/ETS gene fusions had been shown by molecular analysis. This cohort was surveyed for cases that occurred in patients aged 40 years or older, which were then analyzed for their clinical and pathologic features. RESULTS Nine patients between 40 and 65 years of age were found to have tumors positive for EWS/ETS gene fusions. Standard histopathologic and clinical features of these cases, other than age, were similar to those of childhood pPNETs. Patients were initiated on appropriate therapy after molecular analysis confirmed the diagnosis of pPNET. CONCLUSION Identification of an EWS/ETS gene fusion is useful in providing objective evidence of the diagnosis of pPNET in patients over the age of 40 years. This diagnosis should be considered in adults who present with bone and soft tissue SRCTs and appropriate biopsy specimens should be collected for molecular analysis at the time of diagnosis.

scholarly journals Immunohistochemical Markers of Soft Tissue Tumors: Pathologic Diagnosis, Genetic Contributions, and Therapeutic Options

2015 ◽  
Vol 10s1 ◽  
pp. ACI.S32730 ◽  
Author(s):  
David M. Parham
Keyword(s):  
Soft Tissue ◽  
Fusion Gene ◽  
Anticancer Therapy ◽  
Soft Tissue Tumors ◽  
Gene Products ◽  
Ki 67 ◽  
New Techniques ◽  
Immunohistochemical Markers ◽  
Genetic Contributions ◽  
Cell Phenotypes

After ~30 years of widespread usage, immunohistochemistry (IHC) has become a standard method of diagnosis for surgical pathology. Because of the plethora of diagnoses and often subtle nature of diagnostic criteria, IHC finds particular utility in soft tissue tumors. The use of progressively small amounts of tissue for diagnosis highlights the importance of this method. The sensitivity and crispness of IHC stains have progressively improved with the advent of new techniques. Traditionally, IHC detects cell-typic markers that characterize cell phenotypes, such as chromogranin for neuroectodermal tissue, myogenin for skeletal muscle, and cytokeratin for epithelium. However, the advent of genetic discoveries have led to IHC testing for detection of fusion gene products or overexpressed oncogenes associated with deletions and mutations. Proliferation-based markers such as Ki-67 can also be used for prognosis and grading, but more standardization is needed. Development of monoclonal antibody-based pharmaceuticals, such as imatinib or crizotinib, holds the promise of tailored anticancer therapy. IHC thus has assumed importance not only for diagnosis but also for guidance of personalized medicine.

scholarly journals EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1093
Author(s):  
Uta Flucke ◽  
Max M. van Noesel ◽  
Vasiliki Siozopoulou ◽  
David Creytens ◽  
Bastiaan B. J. Tops ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fusion Gene ◽  
Malignant Tumors ◽  
Molecular Techniques ◽  
Bone Lesions ◽  
Fused In Sarcoma ◽  
Molecular Features ◽  
Tata Box Binding Protein

EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.

Cytology of Undifferentiated Round-Cell Sarcomas of Bone and Soft Tissue: Ewing Sarcoma or Not Ewing Sarcoma , That Is the Question

2021 ◽  
pp. 1-12
Author(s):  
Pawel Gajdzis ◽  
Gaëlle Pierron ◽  
Jerzy Klijanienko
Keyword(s):  
Soft Tissue ◽  
Ewing Sarcoma ◽  
Genetic Alterations ◽  
Gene Fusions ◽  
Round Cell ◽  
Ets Transcription Factors ◽  
Myxoid Stroma ◽  
Spindle Cells ◽  
Round Cell Tumors ◽  
Ancillary Studies

<b><i>Background:</i></b> Undifferentiated round-cell sarcomas (URCSs) of soft tissue and bone are a group of clinically heterogeneous tumors. Diagnosis of these malignancies is based mainly on recurrent genetic alterations. The most common and the best known representative of this group is Ewing sarcoma (ES) which is characterized by gene fusions including EWSR1 or FUS and ETS transcription factors family. Other newly described entities are CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and round-cell sarcoma with EWSR1-non-ETS fusions. All these novel tumors are known as Ewing-like sarcomas. <b><i>Summary:</i></b> It is believed that morphologic features of ES and Ewing-like sarcomas vary only slightly or even that cytomorphology is not relevant. But differences are usually obvious, and some cytologic findings, such as spindle cells, connective tissue fragments, or myxoid stroma, are typical for Ewing-like sarcomas but not for ES. Each of these entities is also characterized by different immunoprofiles. The aim of this review was to summarize cytomorphologic and immunohistochemical features of URCS and compare them with other small round-cell tumors. <b><i>Key Messages:</i></b> Cytology can be successfully used in URCS diagnosis as a complementary tool for core-needle biopsy or even alone in selected cases, especially in recurrent and metastatic tumors. Knowing the morphologic and immunohistochemical differences between URCS is essential to provide appropriate ancillary studies and make a definitive diagnosis.

scholarly journals Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes

2015 ◽  
Vol 55 (4) ◽  
pp. 291-310 ◽  
Author(s):  
Fredrik Mertens ◽  
Cristina R. Antonescu ◽  
Felix Mitelman
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Tumors ◽  
Gene Fusions

scholarly journals Dose-Intensified Compared With Standard Chemotherapy for Nonmetastatic Ewing Sarcoma Family of Tumors: A Children's Oncology Group Study

2009 ◽  
Vol 27 (15) ◽  
pp. 2536-2541 ◽  
Author(s):  
Linda Granowetter ◽  
Richard Womer ◽  
Meenakshi Devidas ◽  
Mark Krailo ◽  
Chenguang Wang ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Ewing Sarcoma ◽  
Malignant Tumors ◽  
Alkylating Agents ◽  
Survival Rates ◽  
Chromosomal Translocation ◽  
Soft Tissue Tumors ◽  
Standard Regimen ◽  
Significant Difference ◽  
Eligibility Requirements

Purpose The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue. Methods Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks. Results Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites. Conclusion Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.

Localization of Gallium-67 in Peritoneal Cells by Electron Microscopic Autoradiography

1973 ◽  
Vol 31 ◽  
pp. 404-405
Author(s):  
D. C. Swartzendruber ◽  
Norma L. Idoyaga-Vargas
Keyword(s):  
Clinical Trials ◽  
Soft Tissue ◽  
Tumor Tissue ◽  
Soft Tissue Tumors ◽  
Clinical Usefulness ◽  
Electron Microscopic ◽  
Normal Cells ◽  
Electron Microscopic Autoradiography ◽  
Peritoneal Cells ◽  
Gallium 67

The radionuclide gallium-67 (67Ga) localizes preferentially but not specifically in many human and experimental soft-tissue tumors. Because of this localization, 67Ga is used in clinical trials to detect humar. cancers by external scintiscanning methods. However, the fact that 67Ga does not localize specifically in tumors requires for its eventual clinical usefulness a fuller understanding of the mechanisms that control its deposition in both malignant and normal cells. We have previously reported that 67Ga localizes in lysosomal-like bodies, notably, although not exclusively, in macrophages of the spocytaneous AKR thymoma. Further studies on the uptake of 67Ga by macrophages are needed to determine whether there are factors related to malignancy that might alter the localization of 67Ga in these cells and thus provide clues to discovering the mechanism of 67Ga localization in tumor tissue.

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