Distinct transcriptional signature and immunoprofile of CIC‐DUX4 fusion–positive round cell tumors compared to EWSR1‐rearranged ewing sarcomas: Further evidence toward distinct pathologic entities. Issue 7 (10th April 2014)

• Record Type: Journal Article
• Authors: Specht, Katja; Sung, Yun‐Shao; Zhang, Lei; Richter, Günther H. S.; Fletcher, Christopher D.; Antonescu, Cristina R.
• Is Part Of: Genes, chromosomes & cancer. Volume 53:Issue 7(2014:Jul.)
• Page Start: 622
• Page End: 633
• Publication Date: 2014-04-10
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22172
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Round cell sarcomas harboring <italic>CIC‐DUX4</italic> fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), <italic>CIC‐DUX4</italic>‐positive tumors have generally been classified as ES‐like and managed similarly; however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that <italic>CIC‐DUX4</italic>‐positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between <italic>CIC‐DUX4</italic> tumors and ES. The study group included 21 <italic>CIC‐DUX4</italic>‐positive sarcomas and 20 <italic>EWSR1</italic>‐rearranged ES. Immunohistochemically, <italic>CIC‐DUX4</italic> sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in <italic>EWSR1‐ERG</italic> fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q‐PCR revealed a distinct gene signature associated with <italic>CIC‐DUX4</italic> fusion, with upregulation of <italic>ETS</italic> transcription factors (<italic>ETV4, ETV1</italic>, and <italic>ETV5)</italic> and <italic>WT1</italic>, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of <italic>CIC‐DUX4</italic> sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for <italic>EWSR1</italic> rearrangement. © 2014 Wiley Periodicals, Inc.</p> </abstract>