RT Journal Article
T1 Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets.
A1 Baldauf, Michaela C
A1 Orth, Martin F
A1 Dallmayer, Marlene
A1 Marchetto, Aruna
A1 Gerke, Julia S
A1 Rubio, Rebeca Alba
A1 Kiran, Merve M
A1 Musa, Julian
A1 Knott, Maximilian M L
A1 Ohmura, Shunya
A1 Li, Jing
A1 Akpolat, Nusret
A1 Akatli, Ayse N
A1 Özen, Özlem
A1 Dirksen, Uta
A1 Hartmann, Wolfgang
A1 de Alava, Enrique
A1 Baumhoer, Daniel
A1 Sannino, Giuseppina
A1 Kirchner, Thomas
A1 Grünewald, Thomas G P
K1 BCL11B
K1 Ewing sarcoma
K1 Ewing-like sarcoma
K1 GLG1
K1 immunohistochemistry
AB 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.
YR 2017
FD 2017-08-04
LK https://hdl.handle.net/10668/25138
UL https://hdl.handle.net/10668/25138
LA en
DS RISalud
RD Apr 12, 2025