EWSR1

Gene Summary

Gene:EWSR1; EWS RNA binding protein 1
Aliases: EWS, EWS-FLI1, bK984G1.4
Location:22q12.2
Summary:This gene encodes a multifunctional protein that is involved in various cellular processes, including gene expression, cell signaling, and RNA processing and transport. The protein includes an N-terminal transcriptional activation domain and a C-terminal RNA-binding domain. Chromosomal translocations between this gene and various genes encoding transcription factors result in the production of chimeric proteins that are involved in tumorigenesis. These chimeric proteins usually consist of the N-terminal transcriptional activation domain of this protein fused to the C-terminal DNA-binding domain of the transcription factor protein. Mutations in this gene, specifically a t(11;22)(q24;q12) translocation, are known to cause Ewing sarcoma as well as neuroectodermal and various other tumors. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1 and 14. [provided by RefSeq, Jul 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:RNA-binding protein EWS
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Overview: The EWS (EWSR1) gene is involved in translocations in Ewing's sarcoma, clear cell sarcoma, desmoplastic small round cell tumor and myxoid liposarcoma. The Ewing sarcoma family of tumours is characterised by recurrent translocations that fuse EWS to one of the following genes FLI1 (>90% of cases), ERG, ETV1, E1AF and FEV. In clear cell sarcoma, DSRCT and myxoid liposarcoma EWS is fused to ATF1, WT1 and CHOP respectively.

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (19)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Soft Tissue SarcomaEWSR1 and Soft Tissue Sarcoma View Publications248
Ewing's Sarcomat(11;22)(q24;q12) EWSR1-FLI1 Translocation in Ewing's Sarcoma
The t(11;22)(q24;q12) translocation is present in over 90% of Ewing's sarcoma cases. The resulting EWS-FLI1 fusion gene has been demonstrated to have oncogenic potential. Many alternative forms of the translocation exist, corresponding to variations in the locations of the EWS and FLI1 breakpoints. The most common form, "Type 1", accounts for approximately 60% of cases and consists of the first seven exons of EWS joined to exons 6-9 of FLI1. "Type 2", accounts for approximately 25% of cases and also includes FLI1 exon 5. The type of translocation has been related to prognosis.
View Publications323
Bone Cancer (primary)EWSR1 and Bone Cancer View Publications70
Ewing's SarcomaEWSR1-FLI1 Fusion Transcript Structure and Prognosis?Prognostic
There is wide variation in EWS-FLI1 transcripts. 'Type 1' are created as a result of fusion between exons 7 of EWS and 6 of FLI1, and have reported to be associated with an improved outcome compared to other types of EWS-FLI1 fusions (Zoubek, 1996 and de Alava, 1998). However, in a subsequent COG study of 132 patients (van Doorninck, 2010) concluded that current intensive treatment protocols for localized ESFT have erased the clinical disadvantage that was formerly observed in patients with non-type 1 fusions.
View Publications27
Ewing's Sarcoma t(7;22)(p22;q12) EWS-ETV1 Translocation in Ewing's Sarcoma View Publications24
Desmoplastic Small Round Cell Tumourt(11;22)(p13;q12): EWSR1-WT1 in Desmoplastic Small Round Cell Tumour
DSRCT is a rare and an aggressive malignancy characterised by a translocation of the EWSR1 and WT1 genes, resulting in a EWSR1-WT1 fusion protein.
View Publications16
Salivary Gland CancerEWSR1 and Salivary Gland Cancer View Publications18
Uterine SarcomaEWSR1 and Uterine Cancer View Publications4
Vulvar CancerEWSR1 and Vulvar Cancer View Publications5
Bladder CancerEWSR1 and Bladder Cancer View Publications2
Ewing's Sarcomat(20;22) EWSR1-NFATC2 in Ewing's Sarcoma
A rare variation of the EWSR1 translocation in Ewing's sarcoma involves the NFATC2 gene on chromosome 20.
View Publications4
-EWSR1 and Sweat Gland Neoplasms View Publications0
Bone Cancer (primary)t(18;22)(q23;q12) EWSR1-NFATC1 fusion in hemangioma of the bone
Arbajian et al, 2013 reported a novel t(18;22)(q23;q12) in a hemangioma of the bone.
View Publications1
Ewing's Sarcomat(21;22) EWSR1-ERG Translocations in Ewing's Sarcoma
Ewing's Sarcomat(17;22)(q12;q12) EWSR1-E1AF Translocation in Ewing's Sarcoma
Chondrosarcomat(9;22)(q22;q12) in Extraskeletal Myxoid Chondrosarcoma
Skin Cancert(12; 22)(q13; q12) Translocation in Clear Cell Sarcoma
The t(12;22)(q13;q12) is characteristic of malignant melanoma of soft parts (clear cell sarcoma). This fuses the ATF1 gene on chromosome 12 with the EWS gene on chromosome 22.
-EWSR Translocations in Cutaneous Syncytial Myoepithelioma
Jo et al (2013) reported EWSR1 gene rearrangements detected by FISH in 14/17 (82%) cases of Cutaneous Syncytial Myoepithelioma (usually a benign condition). Testing for potential fusion partners (PBX1, ZNF444, POU5F1, DUX4, ATF1, CREB1, NR4A3, DDIT3, and NFATc2) was negative so the authors suggest that this likely involves a novel fusion partner.
Ewing's Sarcomat(2;22) EWSR1-FEV Translocation in Ewing's Sarcoma

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: EWSR1 (cancer-related)

Jin L, Sui Y, Zhu H, et al.
Primary mediastinal clear cell sarcoma: a case report and review of the literature.
Diagn Pathol. 2017; 12(1):5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Clear cell sarcoma (CCS) is a rare malignant soft-tissue neoplasm that displays melanocytic markers and exhibits striking histopathological features. The tumour has a predilection for the lower extremities and rarely presents in the mediastinum.
CASE PRESENTATION: We present a case of primary mediastinal CCS in a 57-year-old man. Computer tomography (CT) revealed a 12 × 12 × 7.5 cm mass in the anterior mediastinum. Microscopically, the tumour mainly consisted of epithelioid cells with oval vesicular nuclei and eosinophilic cytoplasm. Immunohistochemically, the tumour was positive for human melanoma black 45 (HMB-45) and vimentin but negative for S-100 and Melan-A. Fluorescence in situ hybridisation (FISH) showed a translocation involving the EWSR1 gene region.
CONCLUSION: This report will illustrate that the mediastinum is a potential site for primary CCS and FISH plays an important role in making a conclusive diagnosis.

He T, Surdez D, Rantala JK, et al.
High-throughput RNAi screen in Ewing sarcoma cells identifies leucine rich repeats and WD repeat domain containing 1 (LRWD1) as a regulator of EWS-FLI1 driven cell viability.
Gene. 2017; 596:137-146 [PubMed] Related Publications
A translocation leading to the formation of an oncogenic EWS-ETS fusion protein defines Ewing sarcoma. The most frequent gene fusion, present in 85 percent of Ewing sarcomas, is EWS-FLI1. Here, a high-throughput RNA interference screen was performed to identify genes whose function is critical for EWS-FLI1 driven cell viability. In total, 6781 genes were targeted by siRNA molecules and the screen was performed both in presence and absence of doxycycline-inducible expression of the EWS-FLI1 shRNA in A673/TR/shEF Ewing sarcoma cells. The Leucine rich repeats and WD repeat Domain containing 1 (LRWD1) targeting siRNA pool was the strongest hit reducing cell viability only in EWS-FLI1 expressing Ewing sarcoma cells. LRWD1 had been previously described as a testis specific gene with only limited information on its function. Analysis of LRWD1 mRNA levels in patient samples indicated that high expression associated with poor overall survival in Ewing sarcoma. Gene ontology analysis of LRWD1 co-expressed genes in Ewing tumors revealed association with DNA replication and analysis of differentially expressed genes in LRWD1 depleted Ewing sarcoma cells indicated a role in connective tissue development and cellular morphogenesis. Moreover, EWS-FLI1 repressed genes with repressive H3K27me3 chromatin marks were highly enriched among LRWD1 target genes in A673/TR/shEF Ewing sarcoma cells, suggesting that LRWD1 contributes to EWS-FLI1 driven transcriptional regulation. Taken together, we have identified LRWD1 as a novel regulator of EWS-FLI1 driven cell viability in A673/TR/shEF Ewing sarcoma cells, shown association between high LRWD1 mRNA expression and aggressive disease and identified processes by which LRWD1 may promote oncogenesis in Ewing sarcoma.

Endo A, Tomizawa D, Aoki Y, et al.
EWSR1/ELF5 induces acute myeloid leukemia by inhibiting p53/p21 pathway.
Cancer Sci. 2016; 107(12):1745-1754 [PubMed] Free Access to Full Article Related Publications
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. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1-associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired-end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation-specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21-dependent pathway. The injection of EWSR1/ELF5-transduced NIH3T3 cells into NSG-SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.

Ishiguro M, Yuki M, Fukushige T, et al.
Molecular cytogenetic characterization of two established ESFT cell lines.
Hum Cell. 2017; 30(1):41-48 [PubMed] Related Publications
Ewing's sarcoma/primitive neuroectodermal tumor/Askin's tumor (Ewing`s sarcoma family of tumors: ESFT) is the most common type of malignant tumor of bone and soft tissue in children and young adults, and morphologically is a member of a group of small round cell tumors. We report, here, on the establishment of two human ESFT cell lines, FU-PNET-3 and FU-PNET-4, from the iliac and the chest wall, respectively, the cells of both cell lines were tumorigenic in immunodeficient mice. Histologically, both original and xenograft tumors and cultured cells were composed of small round cells with positive immunoreactivity for CD99 and Nkx2.2. Molecular biological examination demonstrated chimeric transcripts of EWSR1 exon 7 to FLI1 exon 6 in FU-PNET-3 cells, and EWSR1 exon 10 to FLI1 exon 6 in FU-PNET-4 cells. Cytogenetic analysis revealed chromosome translocation t(11;22)(q24;q12) and some secondary changes in both cultured cells. These histological, molecular biological, and cytogenetical findings indicate ESFT in both cell lines. ESFT is well studied, but its recurrent fusion genes are heterogeneous and its biological behaviors are unclear. The FU-PNET-3 and FU-PNET-4 cell lines have been well examined and may become useful tools for studying the genetic and biological behavioral properties of ESFT.

Salet MC, Vogels R, Brons P, et al.
Maturation toward neuronal tissue in a Ewing sarcoma of bone after chemotherapy.
Diagn Pathol. 2016; 11(1):74 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing sarcoma is the second most common bone tumor, occurring mainly in children and young adults. It shows a typical primitive, small round cell morphology and a characteristic fusion oncogene involving EWSR1 and members of the ETS family in most of the cases. Neuronal maturation after chemotherapy is a rare phenomenon and we herein describe such an exceptional case.
CASE PRESENTATION: An 8-year old boy was diagnosed with a Ewing sarcoma in the left femur. On biopsy the morphology was typical and there was an EWSR1-FLI1 gene fusion. He underwent neo-adjuvant chemotherapy and resection of the tumor. On microscopic evaluation, part of the tumor showed ganglioneuroblastoma-like differentiation with expression of neuronal markers. The continued presence of EWSR1 rearrangement in both the blue round cell component and the ganglioneuroblastoma-like component was shown by FISH analysis.
CONCLUSIONS: In conclusion, this case describes the possibility of a Ewing sarcoma to differentiate into a ganglioneuroblastoma-like lesion after neo-adjuvant chemotherapy treatment; the prognostic value of this phenomenon remains questionable.

de Alava E, Marcilla D
Birth and evolution of the desmoplastic small round-cell tumor.
Semin Diagn Pathol. 2016; 33(5):254-61 [PubMed] Related Publications
The first large series of desmoplastic small round cell tumor was reported twenty-five years ago. This article reviews the original characterization of this neoplasm, and the eventual expansion of its clinical and pathological spectrum. Relevant data on its molecular features are summarized, in order to understand the search for therapeutic targets. The challenge ahead is to better know and cure this disease through the finding and validation of actionable therapeutic targets.

Machado I, Navarro L, Pellin A, et al.
Defining Ewing and Ewing-like small round cell tumors (SRCT): The need for molecular techniques in their categorization and differential diagnosis. A study of 200 cases.
Ann Diagn Pathol. 2016; 22:25-32 [PubMed] Related Publications
BACKGROUND: Differentiation of Ewing sarcoma family of tumors (ESFT) and Ewing-like tumors remains problematic. Certain ESFT with morphological and immunohistochemical (IHC) profiles lack the EWSR1-ETS transcript. To improve diagnostic accuracy we investigated the presence of several specific transcripts in 200 small round cell tumors (SRCT) displaying ESFT morphology and immunophenotype in which EWSR1 FISH analysis was non-informative or negative.
DESIGN: 200 tumors (formalin-fixed, paraffin-embedded) were analyzed by RT-PCR. All tumors were tested for EWSR1-ETS, EWSR1/WT1, PAX3/7-FOX01 or SYT/SSX transcripts, and the negative tumors were subsequently analyzed for CIC/DUX4, BCOR/CCNB3 and CIC/FOX04 transcripts.
RESULTS: 133 (66.5%) ESFT displayed one of the above EWSR1-ETS translocations. Three cases (1.5%) revealed the SYT-SSX transcript for Synovial sarcoma, and one (0.5%) a EWSR1-WT1 transcript for Desmoplastic Small Round Cell tumor. The CIC-DUX4 translocation was found in six Ewing-like tumors (3%) with CD99 positivity. The BCOR-CCNB3 gene fusion was observed in 5 tumors (2.5%) displaying round or spindle cells with strong CCNB3 IHC expression in 3 tumors. Moreover, RT-PCR failed to detect any gene fusion transcripts in 19 tumors (9.5%) and were considered "undifferentiated small round cell sarcoma" (SRCS). Molecular biology results were non-informative in 33 SRCTs (16.5%) due to RNA degradation through inadequate fixation and/or decalcification.
CONCLUSION: Our analysis of 200 SRCTs confirms the molecular heterogeneity of neoplasms with ESFT morphology and highlight that molecular studies with RT-PCR including new emerging gene fusion transcripts are mandatory for the diagnosis when EWSR1 FISH is negative or non-informative. The incidence of CIC-DUX4, BCOR-CCNB3 and CIC-FOX04 transcripts was relatively low. A small group of Ewing-like sarcomas or undifferentiated SRCS remains unclassified. Adopting appropriate tissue fixation and processing protocols is important to avoid degradation of fixed/embedded tissue when no frozen tumor is available.

Goh GH, Teh M, Vanecek T, et al.
Primary pulmonary clear cell sarcoma-the first two reported cases.
Virchows Arch. 2016; 469(1):111-7 [PubMed] Related Publications
We report two cases (male patients 50 and 55 years old) of clear cell sarcoma ("melanoma of soft parts") arising in the lung, of which one case showed regional lymph node metastases. Histologically, both tumors displayed varying clear epithelioid and spindle neoplastic cells arranged in storiform and nested growth patterns, separated by thin fibrovascular septa. Immunohistochemical studies demonstrated positive expression of S-100 protein, HMB-45 and Melan-A in one case and S-100 protein only in the other. Fluorescence in situ hybridization showed positive EWSR1 gene rearrangement, and a presence of EWS-ATF1 fusion transcript was confirmed by RT-PCR and sequencing in one case.

Zhang L, Jia Z, Mao F, et al.
Whole-exome sequencing identifies a somatic missense mutation of NBN in clear cell sarcoma of the salivary gland.
Oncol Rep. 2016; 35(6):3349-56 [PubMed] Related Publications
Clear cell sarcoma (CCS) is a rare, low-grade carcinoma commonly located in the distal extremities of young adults involving tendons and aponeuroses. CCS is characterized by its poor prognosis due to late diagnosis, multiple local recurrence, propensity to late metastases, and a high rate of tumor-related mortality. The genetic cause for CCS is thought to be EWSR1 gene translocation. However, CCS lacking a translocation may have other, as yet uncharacterized, genetic mutations that can cause the same pathological effect. A combination of whole‑exome sequencing and Sanger sequencing of cancer tissue and venous blood from a patient diagnosed with CCS of the salivary gland revealed a somatic missense mutation, c.1061C>T (p.P354L), in exon 9 of the Nibrin gene (NBN). This somatic missense mutation led to the conversion of proline to leucine (p.P354L), resulting in deleterious effects for the NBN protein. Multiple-sequence alignments showed that codon 354, where the mutation (c.1061C>T) occurs, is located within a phylogenetically conserved region. In conclusion, we here report a somatic missense mutation c.1061C>T (p.P354L) in the NBN gene in a patient with CCS lacking an EWSR1-ATF1 fusion. Our findings broaden the genotypic spectrum of CCS and provide new molecular insight that should prove useful in the future clinical genetic diagnosis of CCS.

Komura S, Semi K, Itakura F, et al.
An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development.
Stem Cell Reports. 2016; 6(4):592-606 [PubMed] Free Access to Full Article Related Publications
EWS-FLI1, a multi-functional fusion oncogene, is exclusively detected in Ewing sarcomas. However, previous studies reported that rare varieties of osteosarcomas also harbor EWS-ETS family fusion. Here, using the doxycycline-inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also show that sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited an impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrate that EWS-FLI1 contributed to secondary sarcoma development from the sarcoma iPSCs after osteogenic differentiation. These findings demonstrate that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development. This in vitro cancer model using sarcoma iPSCs should provide a unique platform for dissecting relationships between the cancer genome and cellular differentiation.

Vornicova O, Bar-Sela G
Investigational therapies for Ewing sarcoma: a search without a clear finding.
Expert Opin Investig Drugs. 2016; 25(6):679-86 [PubMed] Related Publications
INTRODUCTION: Ewing sarcoma family tumors (ESFT) are a group of aggressive diseases, characterized histologically by small, round, blue cells and genetically by translocation involving EWS and ETS partner genes. The current treatment of localized Ewing sarcoma (ES) requires a multi-disciplinary approach, including multidrug chemotherapy, administrated before and after local treatment, surgery and radiation therapy. Unfortunately, the cure rate of metastatic or refractory/recurrent disease is still very poor.
AREAS COVERED: In this review, the authors summarize the new types of therapy and strategies aimed to improve the prognosis or cure ES. Herein, the authors discuss several preclinical and phase I-II studies with new-targeted therapies. The most studied therapies are insulin-like growth factor receptor (IGF1R) inhibitors but have limited efficacy. Other strategies include Mammalian Target of Rapamycin (mTOR) Inhibition, poly ADP ribose polymerase (PARP) inhibition, vascular endothelial growth factor (VEGF) inhibition, tyrosine kinase inhibitors and telomerase inhibitors, all with limited effectiveness.
EXPERT OPINION: Future treatment strategies should combine one or more targeted therapies with conventional chemotherapy. Some combined modality treatments are under clinical study. However, treatment breakthroughs are still needed to improve the relatively poor prognosis of recurrent/metastatic ESFT.

Ren C, Ren T, Yang K, et al.
Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway.
J Exp Clin Cancer Res. 2016; 35:44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing's sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents. Due to its high malignancy and poor prognosis, identification of novel biomarkers for intervention therapies is necessary to improve outcome. The EWS/FLI1 fusion gene is a characteristic of Ewing's sarcoma in most cases. Sex determining region Y-box 2 (SOX2) is a primary target of EWS/FLI1. It has been identified as an oncogene and linked to apoptotic resistance in several types of cancer. However, its role and regulatory mechanisms in Ewing's sarcoma are largely unknown.
METHODS: We systematically investigated the role of SOX2 in Ewing's sarcoma cell lines, human tissue samples and xenograft models. The expression of SOX2 was detected in Ewing's sarcoma samples by WB and IHC. siRNAs were used to knockdown EWS/FLI1 and SOX2 in A673 and RD-ES cell lines with the efficiencies tested by qRT-PCR and WB. The effect of SOX2 on cell cycle and apoptosis was determined by Flow cytometric and TUNEL assays. Akt overexpression was performed with plasmid. The protein expression of the corresponding factors was examined by WB analysis. Inhibition of SOX2 in vivo was performed by siRNA against SOX2 in xenograft models, and the protein expression of the regulators testified in vitro was examined in xenograft tumors by IHC and WB.
RESULTS: The results confirmed that SOX2 was highly expressed in Ewing's sarcoma and was the target of EWS/FLI1. SOX2 advanced Ewing's sarcoma cell survival and proliferation by regulating p21, p27 and cyclin-E to facilitate G1/S phase transition and mediating caspase-3, PARP via both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2 and XIAP) apoptotic pathways to restrain cell apoptosis. Additionally, SOX2 regulated the cell-cycle progression and apoptosis via activation of the PI3K/Akt signaling pathway. The mechanisms were proved both in vitro and in vivo.
CONCLUSIONS: The results demonstrate that SOX2 played a central role in promoting Ewing's sarcoma cell proliferation in vitro and in vivo with the underlying mechanisms expounded. These findings suggest that SOX2 may serve as a potential biomarker for targeted intervention in Ewing's sarcoma.

Giner J, Isla A, Cubedo R, Tejerina E
Primary Epidural Lumbar Ewing Sarcoma: Case Report and Review of the Literature.
Spine (Phila Pa 1976). 2016; 41(6):E375-8 [PubMed] Related Publications
STUDY DESIGN: Case report.
OBJECTIVE: We present a case of isolated primary epidural lumbar Ewing sarcoma and review the current literature on the standard management. We also propose laminoplasty as safe procedure in this patient population that can provide good stabilization in young people.
SUMMARY OF BACKGROUND DATA: Primary epidural Ewing's sarcoma is a very rare entity. The best generally accepted treatment option in sarcomas is to achieve a gross total resection with safe margins followed by local radiotherapy and chemotherapy. A total resection with safe margins is a great challenge in neurosurgical patients.
METHODS: We present a previously healthy 17-year-old girl who complained of right sciatica with an epidural lumbar mass at L3-L4. She underwent complete resection of the tumor and a laminoplasty, which, in our experience, is a good way to preserve stability.
RESULTS: At surgery, an isolated and noninvasive lesion was identified. Histopathological confirmation of Ewing sarcoma was obtained by immunohistochemical study and EWSR1 gene rearrangement detection. Treatment with 6 months of chemotherapy resulted in no further identifiable lesions by PET and MRI imaging at 4 years postsurgery. The laminoplasty has remained stable.
CONCLUSION: Primary epidural Ewing sarcoma is extremely rare. The detection of the EWSR1 gene rearrangement can help to diagnose these tumors. The decision on how to treat these patients is difficult and can hardly be based on data from the current literature because of the small number of patients. The laminoplasty procedure can be safely performed in the setting of sarcoma of the epidural space.

Gahanbani Ardakani A, Boyle DJ, Elton C
Gastrointestinal clear cell sarcoma-like tumour of the ascending colon.
Ann R Coll Surg Engl. 2016; 98(3):e37-9 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: A clear cell sarcoma-like gastrointestinal tumour (CCSLGT) is a rare malignant soft tissue sarcoma. In the literature, they are sometimes referred to as malignant gastrointestinal neuroectodermal tumours, clear cell sarcomas or osteoclast rich tumours of the gastrointestinal tract.
CASE HISTORY: We present a case of a CCSLGT arising from the ascending colon of a previously well 22-year-old man presenting with abdominal pain and anaemia. Computed tomography of the abdomen and pelvis showed a 7 cm irregular mass in the right flank that seemed to emerge from the proximal transverse colon. A laparoscopic right hemicolectomy was undertaken to remove the mass. Microscopic pathological examination of the specimen revealed sections of spindle to oval cells with monomorphic nuclei and scant cytoplasm. The cells were arranged in a striking perivascular growth pattern with microcytic breakdown and pseudopapillary formation. Immunohistochemistry analysis showed that the tumour cells removed expressed S100 protein, and were negative for smooth muscle actin, desmin, CD34, CD117, DOG1, HMB-45 and MNF116. Additionally, cytogenetic testing identified EWSR1 gene rearrangement, which was observed by interphase fluorescence in situ hybridisation.
CONCLUSIONS: A complex tumour, a CCSLGT can be thought of in simple terms as a gastrointestinal tract tumour that is S100 protein positive, osteoclast rich, HMB-45 negative and compromises a t(12;22)(q13;q12) gene translocation. These simplified CCSLGT characteristics seem to be described and classified under different aliases in the literature, which makes it difficult to accurately predict the appropriate diagnostic and therapeutic modality required to provide the best clinical care. Given that this case report describes the fourth CCSLGT of primary colonic origins, it may aid future targeted therapies as well as offering epidemiological evidence on prevalence and prognosis.

Åman P, Dolatabadi S, Svec D, et al.
Regulatory mechanisms, expression levels and proliferation effects of the FUS-DDIT3 fusion oncogene in liposarcoma.
J Pathol. 2016; 238(5):689-99 [PubMed] Related Publications
Fusion oncogenes are among the most common types of oncogene in human cancers. The gene rearrangements result in new combinations of regulatory elements and functional protein domains. Here we studied a subgroup of sarcomas and leukaemias characterized by the FET (FUS, EWSR1, TAF15) family of fusion oncogenes, including FUS-DDIT3 in myxoid liposarcoma (MLS). We investigated the regulatory mechanisms, expression levels and effects of FUS-DDIT3 in detail. FUS-DDIT3 showed a lower expression than normal FUS at both the mRNA and protein levels, and single-cell analysis revealed a lack of correlation between FUS-DDIT3 and FUS expression. FUS-DDIT3 transcription was regulated by the FUS promotor, while its mRNA stability depended on the DDIT3 sequence. FUS-DDIT3 protein stability was regulated by protein interactions through the FUS part, rather than the leucine zipper containing DDIT3 part. In addition, in vitro as well as in vivo FUS-DDIT3 protein expression data displayed highly variable expression levels between individual MLS cells. Combined mRNA and protein analyses at the single-cell level showed that FUS-DDIT3 protein expression was inversely correlated to the expression of cell proliferation-associated genes. We concluded that FUS-DDIT3 is uniquely regulated at the transcriptional as well as the post-translational level and that its expression level is important for MLS tumour development. The FET fusion oncogenes are potentially powerful drug targets and detailed knowledge about their regulation and functions may help in the development of novel treatments.

Theisen ER, Pishas KI, Saund RS, Lessnick SL
Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting.
Oncotarget. 2016; 7(14):17616-30 [PubMed] Free Access to Full Article Related Publications
Ewing sarcoma is an aggressive primary pediatric bone tumor, often diagnosed in adolescents and young adults. A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1. Nearly 85% of cases express the EWS-FLI protein which functions as a transcription factor and drives oncogenesis. As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma. However, transcription factors are notoriously difficult targets for the development of small molecules. Improved understanding of the oncogenic mechanisms employed by EWS-FLI to hijack normal cellular programming has uncovered potential novel approaches to pharmacologically block EWS-FLI function. In this review we examine targeting the chromatin regulatory enzymes recruited to conspire in oncogenesis with a focus on the histone lysine specific demethylase 1 (LSD1). LSD1 inhibitors are being aggressively investigated in acute myeloid leukemia and the results of early clinical trials will help inform the future use of LSD1 inhibitors in sarcoma. High LSD1 expression is observed in Ewing sarcoma patient samples and mechanistic and preclinical data suggest LSD1 inhibition globally disrupts the function of EWS-ETS proteins.

Kovar H, Amatruda J, Brunet E, et al.
The second European interdisciplinary Ewing sarcoma research summit--A joint effort to deconstructing the multiple layers of a complex disease.
Oncotarget. 2016; 7(8):8613-24 [PubMed] Free Access to Full Article Related Publications
Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second "European interdisciplinary Ewing sarcoma research summit" assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.

Grohar PJ, Kim S, Rangel Rivera GO, et al.
Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma.
Cell Rep. 2016; 14(3):598-610 [PubMed] Free Access to Full Article Related Publications
Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.

Rekhi B, Joshi S, Panchwagh Y, et al.
Clinicopathological features of five unusual cases of intraosseous myoepithelial carcinomas, mimicking conventional primary bone tumours, including EWSR1 rearrangement in one case.
APMIS. 2016; 124(4):278-90 [PubMed] Related Publications
Primary intraosseous myoepithelial tumours, including carcinomas are rare tumours. The concept of histopathological spectrum of these tumours is evolving. We describe clinicopathological and immunohistochemical features of five myoepithelial carcinomas, including molecular cytogenetic results in one case. There were five male patients within age-range of 8-40 years (median = 26). Four tumours occurred in the long bones, including two tumours, each, in the femur and fibula, respectively, while a single tumour occurred in the proximal phalanges. Tumour size (n = 3 cases) varied from 5.6 to 8.6 cm. On radiological imaging, most tumours appeared as expansile, lytic and destructive lesions. Two tumours appeared as sclerotic lesions. Two cases were referred with diagnoses of chondrosarcomas and a single case was referred with two different diagnoses, including an adamantinoma and an osteosarcoma. Histopathological examination in all these cases showed multinodular tumours comprising mostly polygonal cells, exhibiting moderate nuclear atypia and interspersed mitotic figures within a stroma containing variable amount of myxoid, chondroid, hyalinised and osteoid-like material. Three tumours revealed prominent squamous differentiation. By immunohistochemistry, tumour cells were positive for EMA (5/5), pan CK (AE1/AE3) (3/3), CK5/6 (4/4), CK MNF116 (1/1), S100 protein (5/5) and GFAP (3/5). The first tumour revealed EWSR1 rearrangement. The first patient, 10 months after tumour resection and a simultaneous lung metastatectomy, is free-of-disease (FOD). The second patient, 11 months after tumour resection is FOD. The third and fourth patients underwent wide resections and are on follow-up. The fifth patient underwent resections, including a lung metastatectomy. Primary intraosseous myoepithelial carcinomas are rare and mimic conventional primary bone tumours. Some primary intraosseous myoepithelial carcinomas display EWSR1 rearrangement. Squamous differentiation may be considered as an addition to their evolving histopathological spectrum. Immunohistochemical stains constitute as a necessary tool for arriving at the correct diagnosis in such cases, which has treatment implications. Surgical resection remains the treatment mainstay.

Costigan DC, Doyle LA
Advances in the clinicopathological and molecular classification of cutaneous mesenchymal neoplasms.
Histopathology. 2016; 68(6):776-95 [PubMed] Related Publications
In recent years, there have been several important refinements in the classification of cutaneous mesenchymal neoplasms, including the description of new tumour types, along with the identification of novel and recurrent molecular genetic findings. In addition to providing new insights into tumour biology, many of these advances have had significant clinical consequences with regard to diagnostics, management, and prognostication. Newly described entities include pseudomyogenic haemangioendothelioma, haemosiderotic fibrolipomatous tumour, and fibroblastic connective tissue naevus, which are reviewed in the context of the principal differential diagnoses and significant clinical implications. Genetic characterization of several soft tissue tumour types that occur in the skin has resulted in the identification of diagnostically useful markers: ALK gene rearrangement with corresponding ALK protein expression by immunohistochemistry in epithelioid fibrous histiocytoma; the WWTR1-CAMTA1 fusion gene with CAMTA1 protein expression in epithelioid haemangioendothelioma; MYC amplification and overexpression in radiation-associated angiosarcoma; and EWSR1 gene rearrangement in cutaneous myoepithelial tumours. Finally, the classification of intradermal smooth muscle tumours and unclassified/pleomorphic dermal sarcoma has been refined, resulting in both improved classification and improved prognostication. Many of the tumour types listed above are encountered not only by specialist dermatopathologists, but also by practising general surgical pathologists, and this review should therefore provide a widely applicable update on the histological and molecular classification of cutaneous mesenchymal neoplasms, along with the appropriate use of ancillary diagnostic tests, in particular immunohistochemistry, in the evaluation of such lesions and their histological mimics.

Specht K, Zhang L, Sung YS, et al.
Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas.
Am J Surg Pathol. 2016; 40(4):433-42 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose because of overlapping morphologic, immunohistochemical, and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4-related fusions, whereas another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44-year-old man, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by reverse transcription polymerase chain reaction and fluorescence in situ hybridization techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC, and BCOR-CCNB3 abnormalities for BCOR break-apart probes by fluorescence in situ hybridization to detect potential recurrent BCOR gene rearrangements outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, whereas no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3-positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared with classic Ewing's sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SBRCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion-positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs, which presented in young adults, with a variable anatomic distribution. Furthermore, BCOR-rearranged tumors often displayed spindle cell areas, either well defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma.

Yuan CT, Hsieh MS
Tigroid background in cytology of hyalinizing clear cell carcinoma of the salivary gland.
Diagn Cytopathol. 2016; 44(4):338-41 [PubMed] Related Publications
Hyalinizing clear cell carcinoma (HCCC) is a rare and low grade salivary gland carcinoma with a unique recurrent EWSR1 gene translocation. HCCC most commonly arises from intraoral minor salivary glands and its cytological features have not been well evaluated. We report a 28-year-old man with palatal HCCC and emphasize the "tigroid background" and metachromatic matrix observed in scrape cytology. This "tigroid background," usually associated with glycogen-rich clear cell tumors, is an important cytological feature of HCCC. Awareness of this feature can do great help in pathological research and diagnosis.

Chen S, Deniz K, Sung YS, et al.
Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH.
Genes Chromosomes Cancer. 2016; 55(4):340-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The genetics of Ewing sarcoma (ES) are characterized by a canonical fusion involving EWSR1 gene and a member of the ETS family of transcription factors, such as FLI1 and ERG. In fact, ERG gene rearrangements represent the second most common molecular alteration, with EWSR1-ERG being identified in 5-10% of cases, while only a handful of reports document a FUS-ERG fusion. In this study, we focus on ES with ERG gene abnormalities, specifically to investigate the prevalence and clinicopathologic features of FUS-ERG fusions in a large cohort of small blue round cell tumors (SBRCTs) and compare to the eight reported FUS-positive ES. Among the 85 SBRCTs tested, seven (8.2%) cases harbored FUS gene rearrangements; six fused to ERG and one with FEV. During this investigation we came across a number of ERG-rearranged ES lacking both EWSR1 and FUS abnormalities by FISH. In one case, RNA sequencing identified an EWSR1-ERG transcript despite the negative EWSR1 rearrangements by FISH. Additional 3-color FISH fusion assay demonstrated the fusion of EWSR1 and ERG signals in all four cases negative for break-apart EWSR1 FISH. These results emphasize a potential pitfall of relying on EWSR1 FISH assay alone for diagnosis of ES. In cases with classic morphology and/or strong CD99 and ERG immunoreactivity, additional molecular testing should be applied, such as ERG FISH or RT-PCR/next generation sequencing, for a more definitive diagnosis. Although our study group is small, there were no differences noted between the clinical, morphologic features and immunoprofile of the different subsets of ERG-rearranged SBRCTs.

Yoshida A, Goto K, Kodaira M, et al.
CIC-rearranged Sarcomas: A Study of 20 Cases and Comparisons With Ewing Sarcomas.
Am J Surg Pathol. 2016; 40(3):313-23 [PubMed] Related Publications
The CIC gene rearrangement exists in a subset of small round cell sarcomas. As the nosologic relationship of these sarcomas to Ewing sarcomas remains undetermined, we examined 20 CIC-rearranged sarcomas to compare their clinicopathologic features with those of Ewing sarcomas. The CIC-rearranged sarcomas were from a group of 14 men and 6 women with a median age of 24.5 years. The primary tumor sites included the limbs, trunk wall, internal trunk, lung, cerebrum, and pharynx. A comparison of the demographic and clinical characteristics of the 20 patients with CIC-rearranged sarcomas with those of the 53 near-consecutive patients with EWSR1-rarranged Ewing sarcomas showed that there were no differences with respect to their ages and sexes. Although none of the CIC-rearranged sarcomas arose in the bone, 40% of the Ewing sarcomas primarily affected the skeleton. The overall survival of patients with Ewing sarcomas was significantly better than that for patients with CIC-rearranged 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. Distinguishing immunohistochemical features included heterogenous CD99 reactivity, nuclear WT1 expression, and calretinin expression in the CIC-rearranged sarcomas and NKX2.2 expression in the Ewing sarcomas. CIC-rearranged sarcomas are distinct from Ewing sarcomas clinically, morphologically, and immunohistochemically, and they should be considered a separate entity rather than being grouped within the same family of tumors.

Owosho AA, Ko E, Rosenberg HI, et al.
Primary Ewing Family of Tumors of the Jaw Has a Better Prognosis Compared to Tumors of Extragnathic Sites.
J Oral Maxillofac Surg. 2016; 74(5):973-81 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Primary Ewing sarcoma of the jaw is rare. The aim of this study was to describe new cases of primary Ewing sarcoma of the jaw and investigate reported prognostic factors of Ewing sarcoma in this series and treatment outcome.
MATERIALS AND METHODS: Six patients with primary Ewing sarcoma of the jaw were treated at the Memorial Sloan Kettering Cancer Center (MSKCC) from 1992 through 2013. Clinical data, pathology reports, treatment prescribed, treatment regimens, outcome, and follow-up information were reviewed.
RESULTS: Five of 6 patients were female and 5 cases were in the mandible. No patient presented with metastatic disease at diagnosis. All cases were positive for CD99, and 3 patients with genetic confirmation were positive for EWS-FLI1 fusion or EWSR1 gene rearrangement. All patients received induction multiagent chemotherapy and surgical resection and 2 patients received adjuvant radiotherapy. Total (grade IV) or nearly total (grade III) tumor necrosis in 3 of 5 patients (60%) assessed for histologic response to chemotherapy indicated intense sensitivity. All patients were alive and free of disease, with no history of local recurrence, at a median follow-up period of 6.5 years.
CONCLUSION: Patients with primary Ewing sarcoma of the jaw have a good prognosis and metastasis is an uncommon occurrence at initial presentation.

Nugent M
microRNA and Bone Cancer.
Adv Exp Med Biol. 2015; 889:201-30 [PubMed] Related Publications
MicroRNA molecules have a variety of roles in cellular development and proliferation processes, including normal osteogenesis. These effects are exerted through post-translational inhibition of target genes. Altered miRNA expression has been demonstrated in several cancers, both in the tumor tissue and in the peripheral circulation. This may influence carcinogenesis if the specific miRNA targets are encoded by tumor suppressor genes or oncogenes. To date, most research investigating the role of microRNAs and primary bone tumors has focused on osteosarcoma and Ewing sarcoma. Several microRNAs including the miR-34 family have been implicated in osteosarcoma tumorigenesis via effects on the Notch signaling pathway. Progression, invasion, and metastasis of osteosarcoma tumor cells is also influenced by microRNA expression. In addition, microRNA expression may affect the response to chemotherapy in osteosarcoma and thus hold potential for future use as either a prognostic indicator or a therapeutic target. The EWS-FLI1 fusion protein produced in Ewing sarcoma has been shown to induce changes in miRNA expression. MicroRNA expression profiling may have some potential for prediction of disease progression and survival in Ewing sarcoma. There is limited evidence to support a role for microRNAs in other primary bone tumors, either malignant or benign; however, early work is suggestive of involvement in chondrosarcoma, multiple osteochondromatosis, and giant cell tumors of bone.

Leduc C, Zhang L, Öz B, et al.
Thoracic Myoepithelial Tumors: A Pathologic and Molecular Study of 8 Cases With Review of the Literature.
Am J Surg Pathol. 2016; 40(2):212-23 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Thoracic myoepithelial tumors (MTs) are a rare group of tumors showing predominant or exclusive myoepithelial differentiation. They are poorly characterized from both a morphologic and genetic standpoint, in particular features that separate benign from malignant behavior. We examined the histologic and immunohistochemical features of 8 primary thoracic MTs and performed fluorescence in situ hybridization for EWSR1, FUS, PLAG1, and HMGA2, as well as several partner genes. Half (4/8) of the MTs occurred in large airways, and 3 had infiltrative borders. All cases showed immunoreactivity for epithelial markers, in conjunction with S100 protein or myogenic markers. MTs showed morphologic characteristics analogous to MTs at other sites, with no tumors having ductal differentiation. Necrosis and/or lymphovascular invasion was present in 5 cases, with mitotic activity ranging from 0 to 6 mitoses/2 mm² (mean 1). Metastases occurred in 2 cases, and no patients died of disease. Gene rearrangements were identified in half of the cases, with EWSR1-PBX1, EWSR1-ZNF444, and FUS-KLF17 fusions identified in 1 case each and 1 case having EWSR1 rearrangement with no partner identified. No cases were found to have HMGA2 or PLAG1 abnormalities. Compared with fusion-negative tumors, fusion-positive tumors tended to occur in patients who were younger (50 vs. 58 y), female (1:3 vs. 3:1 male:female ratio), and demonstrated predominantly spindle and clear cell morphology. Using a combined data set of our case series with 16 cases from the literature, poor prognosis was significantly correlated with metastases (P=0.003), necrosis (P=0.027), and ≥5 mitoses/2 mm²/10 high-power field (P=0.005). In summary, we identify a subset of thoracic MTs harboring rearrangements in EWSR1 or FUS, and our data suggest that necrosis and increased mitotic activity correlate with aggressive clinical behavior.

Hensel T, Giorgi C, Schmidt O, et al.
Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma.
Oncotarget. 2016; 7(2):1451-63 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.

Safavi S, Järnum S, Vannas C, et al.
HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo.
Oncotarget. 2016; 7(1):433-45 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin. Treatment with RET specific kinase inhibitor Vandetanib failed to reduce RET phosphorylation and inhibit cell growth, suggesting that other RTKs may phosphorylate RET. A screening pointed out EGFR and ERBB3 as the strongest expressed phosphorylated RTKs in MLS cells. We show that ERBB3 formed nuclear and cytoplasmic complexes with RET and both RTKs were previously reported to form complexes with EGFR. The formation of RTK hetero complexes could explain the observed Vandetanib resistence in MLS. EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death. Treatment of MLS xenograft carrying Nude mice resulted in massive necrosis, rupture of capillaries and hemorrhages in tumor tissues. We conclude that complex formation between RET and other RTKs may cause RTK inhibitor resistance. HSP90 inhibitors can overcome this resistance and are thus promising drugs for treatment of MLS/RCLS.

Kastrinos F, Ojha RP, Leenen C, et al.
Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.
J Natl Cancer Inst. 2016; 108(2) [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers.
METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided.
RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%.
CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family.

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