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Title: Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information
Author: Koelsche, Christian
Hartmann, Wolfgang
Schrimpf, Daniel
Stichel, Damian
Jabar, Susanne
Ranft, Andreas
Reuss, David E.
Sahm, Felix
Jones, David T. W.
Bewerunge-Hudler, Melanie
Trautmann, Marcel
Klingebiel, Thomas
Vokuhl, Christian
Gessler, Manfred
Wardelmann, Eva
Petersen, Iver
Baumhoer, Daniel
Flucke, Uta
Antonescu, Cristina
Esteller, Manel
Fröhling, Stefan
Kool, Marcel
Pfister, Stefan M.
Mechtersheimer, Gunhild
Dirksen, Uta
von Deimling, Andreas
Keywords: Sarcoma d'Ewing
Ewing's sarcoma
Issue Date: Aug-2018
Publisher: Nature Publishing Group
Abstract: Undifferentiated solid tumors with small blue round cell histology and expression of CD99 mostly resemble Ewing sarcoma. However, they also may include other tumors such as mesenchymal chondrosarcoma, synovial sarcoma, or small cell osteosarcoma. Definitive classification usually requires detection of entity-specific mutations. While this approach identifies the majority of Ewing sarcomas, a subset of lesions remains unclassified and, therefore, has been termed 'Ewing-like sarcomas' or small blue round cell tumors not otherwise specified. We developed an approach for further characterization of small blue round cell tumors not otherwise specified using an array-based DNA-methylation profiling approach. Data were analyzed by unsupervised clustering and t-distributed stochastic neighbor embedding analysis and compared with a reference methylation data set of 460 well-characterized prototypical sarcomas encompassing 18 subtypes. Verification was performed by additional FISH analyses, RNA sequencing from formalin-fixed paraffin-embedded material or immunohistochemical marker analyses. In a cohort of more than 1,000 tumors assumed to represent Ewing sarcomas, 30 failed to exhibit the typical EWS translocation. These tumors were subjected to methylation profiling and could be assigned to Ewing sarcoma in 14 (47%), to small blue round cell tumors with CIC alteration in 6 (20%), to small blue round cell tumors with BCOR alteration in 4 (13%), to synovial sarcoma and to malignant rhabdoid tumor in 2 cases each. One single case each was allotted to mesenchymal chondrosarcoma and adamantinoma. 12/14 tumors classified as Ewing sarcoma could be verified by demonstrating either a canonical EWS translocation evading initial testing, by identifying rare breakpoints or fusion partners. The methylation-based assignment of the remaining small blue round cell tumors not otherwise specified also could be verified by entity-specific molecular alterations in 13/16 cases. In conclusion, array-based DNA-methylation analysis of undifferentiated tumors with small blue round cell histology is a powerful tool for precisely classifying this diagnostically challenging tumor group.
Note: Versió postprint del document publicat a:
It is part of: Modern Pathology, 2018, vol. 31, num. 8, p. 1246-1256
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ISSN: 0893-3952
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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