Open AccessRobust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets
Author(s) -
Michaela C. Baldauf,
Martin F. Orth,
Marlene Dallmayer,
Aruna Marchetto,
Julia S. Gerke,
Rebeca Alba Rubío,
Merve Meryem Kıran,
Julian Musa,
Max Knott,
Shunya Ohmura,
Jing Li,
Nusret Akpolat,
Ayşe Nur Akatlı,
Özlem Özen,
Uta Dirksen,
Wolfgang Hartmann,
Enrique de Álava,
Daniel Baumhoer,
Giuseppina Sannino,
Thomas Kirchner,
Thomas G. P. Grünewald
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.20098
Subject(s) - cd99 , fli1 , immunohistochemistry , sarcoma , ewing's sarcoma , desmoplastic small round cell tumor , tissue microarray , pathology , cancer research , biology , medicine , chromosomal translocation , gene , genetics , vimentin
Ewing 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.