Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets

Baldauf, Michaela C.; Orth, Martin F.; Dallmayer, Marlene; Marchetto, Aruna; Gerke, Julia S.; Rubío, Rebeca Alba; Kıran, Merve Meryem; Musa, Julian; Knott, Maximilian M. L.; Ohmura, Shunya; Li, Jing; Akpolat, Nusret; Akatlı, Ayşe Nur; Özen, Özlem; Dirksen, Uta; Hartmann, Wolfgang; Álava, Enrique de; Baumhoer, Daniel; Sannino, Giuseppina; Kirchner, Thomas; Grünewald, Thomas G.P.

doi:10.1101/158766

Cited by 14 publications

(19 citation statements)

References 54 publications

(56 reference statements)

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“…1a). These data were validated on the protein level in a tissue microarray 23,24 comprising the same normal tissue types and cancer entities (Fig. 1b,c).…”

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 81%

“…To explore the expression pattern of SOX6, we took advantage of a well-curated set of >750 DNA microarrays, which we established previously 23,24 , comprising 18 representative normal tissues types and 10 cancer entities. Comparative analyses revealed that SOX6 is overexpressed in EwS relative to normal tissues and other cancers (Fig.…”

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 99%

“…For IHC, 4-µm sections were cut and antigen retrieval was carried out by heat treatment with Target Retrieval Solution (S1699, Agilent Technologies, Germany). The slides were stained with either polyclonal anti-SOX6 antibody raised in rabbit (1:1,600; HPA003908, Atlas Antibodies, Sweden) or with monoclonal anti-Ki67 raised in rabbit (1: was carried out in analogy to scoring of hormone receptor Immune Reactive Score (IRS) ranging from 0-12 as previously described 23 . The percentage of cells with expression of the given antigen was scored and classified in five grades (grade 0 = 0−19%, grade 1 = 20−39%, grade 2 = 40−59%, grade 3 = 60−79% and grade 4 = 80−100%).…”

Section: Immunohistochemistry (Ihc) and Immunoreactivity Scoring (Irs)mentioning

confidence: 99%

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Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Marchetto¹,

Ohmura²,

Orth³

et al. 2019

Preprint

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Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcriptionfactors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAAmicrosatellites (mSats) as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 -a physiological driver of proliferation of osteo-chondrogenic progenitors -by binding to an intronic GGAA-mSat, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments, we discovered that SOX6 interferes with the antioxidant system resulting in constitutively elevated reactive oxygen species (ROS) levels that create a therapeutic vulnerability toward the ROS-inducing drug Elesclomol. Collectively, our results exemplify how aberrant activation of a developmentaltranscription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.Ewing sarcoma (EwS) is the second most common bone or soft-tissue cancer in children and adolescents 1 . Even though the cell of origin of EwS is still debated, increasing evidence suggests that it may arise from mesenchymal stem cell (MSC)-derived early committed osteochondrogenic progenitors 2,3 . Indeed, EwS cells display a highly undifferentiated and embryonal phenotype. Clinically, EwS is a rapidly metastasizing cancer, and ~25% of cases are metastatic at initial diagnosis 1 . While great advances in treatment of localized disease have been achieved, established therapies still have limited success in advanced stages despite high toxicity 1 . Thus, more specific and in particular less toxic therapies are urgently required.As a genetic hallmark, EwS tumors express chimeric EWSR1-ETS (EwS breakpoint region 1 -E26 transformation specific) fusion oncoproteins generated through fusion of the EWSR1 gene and variable members of the ETS-family of transcription factors (TF), most commonly FLI1 (85% of all cases) 4,5 . Prior studies demonstrated that EWSR1-FLI1 acts as a pioneer transcription factor that massively rewires the tumor transcriptome ultimately promoting the malignant phenotype of EwS 6,7 . This is in part mediated through interference with and/or aberrant activation of developmental pathways 3,8 . Remarkably, EWSR1-FLI1 regulates approximately 40% of its target genes by binding to otherwise non-functional GGAA-

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“…1a). These data were validated on the protein level in a tissue microarray 23,24 comprising the same normal tissue types and cancer entities (Fig. 1b,c).…”

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 81%

Section: Sox6 Is Highly But Variably Expressed In Ewsmentioning

confidence: 99%

Section: Immunohistochemistry (Ihc) and Immunoreactivity Scoring (Irs)mentioning

confidence: 99%

See 1 more Smart Citation

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Marchetto¹,

Ohmura²,

Orth³

et al. 2019

Preprint

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“…Two recent large series (assessing a combined 70 cases) both reported a sensitivity of 93% 105,106. However, assessments across the spectrum of round cell tumors have shown this marker is not entirely specific 105,107. Consequently, it is currently best utilized as part of a wider panel; immunohistochemistry has not supplanted the use of molecular confirmation in difficult/atypical cases.…”

mentioning

confidence: 99%

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

Anderson

Hornick

2018

Genes Chromosomes & Cancer

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Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high‐throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan‐TRK); amplifications in well‐differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta‐catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.

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“…In addition, strong and diffuse nuclear staining for WT1 and ETV4 aids in their distinction from Ewing sarcoma or BCOR-rearranged round cell sarcoma [9]. A similar situation could be seen in BCOR [10], or even in NFATc2-rearranged sarcoma [11].…”

Section: What Makes a Group Of Tumors Become A Clinical Entity? A Simmentioning

confidence: 94%

What's in a name? Molecular subclassification of sarcomas creates fresh challenges

Díaz‐Martín¹,

Biscuola²,

Benoit

et al. 2019

The Journal of Pathology

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This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR‐rearranged sarcomas, CIC‐fused sarcomas) and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high‐throughput techniques could be applied to sarcoma diagnosis in the short term. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets

Cited by 14 publications

References 54 publications

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

What's in a name? Molecular subclassification of sarcomas creates fresh challenges

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