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

Basit Öğe Kaydı
dc.authoridAKPOLAT, Nusret/0000-0002-9138-2117
dc.authoridOhmura, Shunya/0000-0002-0930-5172
dc.authoridÖzen, Özlem/0000-0002-9082-1317
dc.authoridAKATLI, AYSE NUR/0000-0002-9677-2456
dc.authoridde Alava, Enrique/0000-0001-8400-046X
dc.authoridGrünewald, Thomas G. P./0000-0003-0920-7377
dc.authoridkiran, merve Meryem/0000-0003-2498-0472
dc.authorwosidAKPOLAT, Nusret/ABF-6986-2020
dc.authorwosidKnott, Maximilian/AAD-4315-2021
dc.authorwosidOhmura, Shunya/HGF-1322-2022
dc.authorwosidÖzen, Özlem/AAK-4468-2021
dc.authorwosidAKATLI, AYSE NUR/ABH-4455-2020
dc.authorwosidde Alava, Enrique/GOH-0368-2022
dc.authorwosidDirksen, Uta/AGX-8472-2022
dc.contributor.authorBaldauf, Michaela C.
dc.contributor.authorOrth, Martin F.
dc.contributor.authorDallmayer, Marlene
dc.contributor.authorMarchetto, Aruna
dc.contributor.authorGerke, Julia S.
dc.contributor.authorRubio, Rebeca Alba
dc.contributor.authorKiran, Merve M.
dc.date.accessioned2024-08-04T20:44:14Z
dc.date.available2024-08-04T20:44:14Z
dc.date.issued2018
dc.departmentİnönü Üniversitesien_US
dc.description.abstractEwing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4-, BCOR-CCNB3-, EWSR1-NFATc2-, and EWSR1-ETS-translocated sarcomas are distinct entities, and revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma. Their high expression was validated by immunohistochemistry and proved to depend on EWSR1-FLI1-binding to highly active proximal super-enhancers. Automated cut-off-finding and combination-testing in a tissue-microarray comprising 174 samples demonstrated that detection of high BCL11B and/or GLG1 expression is sufficient to reach 96% specificity for Ewing sarcoma. While 88% of tested Ewing-like sarcomas displayed strong CD99-immunoreactivity, none displayed combined strong BCL11B-and GLG1-immunoreactivity. Collectively, we show that ATP1A1, BCL11B, and GLG1 are EWSR1-FLI1 targets, of which BCL11B and GLG1 offer a fast, simple, and cost-efficient way to diagnose Ewing sarcoma by immunohistochemistry. These markers may significantly reduce the number of misdiagnosed patients, and thus improve patient care.en_US
dc.description.sponsorshipKind-Philipp-Foundation; Deutsche Stiftung fur Junge Erwachsene mit Krebs; German National Academic Foundation; 'Verein zur Forderung von Wissenschaft und Forschung an der Medizinischen Fakultat der LMU Munchen' (WiFoMed); Daimler and Benz Foundation; Reinhard Frank Foundation; Friedrich-Baur-Stiftung; LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative; Mehr LEBEN fur krebskranke Kinder - Bettina-Brau-Stiftung; Fritz-Thyssen Foundation [FTF-40.15.0.030MN]; Wilhelm-Sander-Foundation [2016.167.1]; German Cancer Aid [DKH-111886, DKH-70112257, DKH-108128]; EU FP7 and TRANSCAN EraNet - PROVABES [01KT1310]; EU-FP7 EEC [602856-2]en_US
dc.description.sponsorshipThis work was supported by the Kind-Philipp-Foundation (to J.M., M.C.B., M.F.O., M.D., A.M, and G.S.), the 'Deutsche Stiftung fur Junge Erwachsene mit Krebs' (to M.D.), the German National Academic Foundation (to M.C.B. and M.M.L.K.), the 'Verein zur Forderung von Wissenschaft und Forschung an der Medizinischen Fakultat der LMU Munchen' (WiFoMed; to T.G.P.G.), the Daimler and Benz Foundation in cooperation with the Reinhard Frank Foundation (to T.G.P.G.), the Friedrich-Baur-Stiftung (to T.G.P.G.) by LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative (to T.G.P.G.), the 'Mehr LEBEN fur krebskranke Kinder - Bettina-Brau-Stiftung' (to T.G.P.G.), the Fritz-Thyssen Foundation (FTF-40.15.0.030MN, to T.G.P.G. and G.S.), the Wilhelm-Sander-Foundation (2016.167.1 to T.G.P.G.), and the German Cancer Aid (DKH-111886 and DKH-70112257 to T.G.P.G.; DKH-108128 to U.D.), EU FP7 and TRANSCAN EraNet - PROVABES [01KT1310], EU-FP7 EEC [602856-2] to U.D.en_US
dc.identifier.doi10.18632/oncotarget.20098
dc.identifier.endpage1601en_US
dc.identifier.issn1949-2553
dc.identifier.issue2en_US
dc.identifier.pmid29416716en_US
dc.identifier.scopus2-s2.0-85039996227en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage1587en_US
dc.identifier.urihttps://doi.org/10.18632/oncotarget.20098
dc.identifier.urihttps://hdl.handle.net/11616/98103
dc.identifier.volume9en_US
dc.identifier.wosWOS:000419623200009en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherImpact Journals Llcen_US
dc.relation.ispartofOncotargeten_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectEwing sarcomaen_US
dc.subjectEwing-like sarcomaen_US
dc.subjectimmunohistochemistryen_US
dc.subjectBCL11Ben_US
dc.subjectGLG1en_US
dc.titleRobust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targetsen_US
dc.typeArticleen_US

Dosyalar

Koleksiyon

WoS İndeksli Yayınlar Koleksiyonu
PubMed İndeksli Yayın Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu