High prevalence ofCICfusion with double-homeobox (DUX4) transcription factors inEWSR1-negative undifferentiated small blue round cell sarcomas

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Primitive round cell sarcomas of childhood and young adults have been problematic to diagnose and classify. Our goal was to investigate the pathologic and molecular characteristics of small blue round cell tumors (SBRCT) that remained unclassified after exhaustive immunohistochemistry and molecular screening to exclude known sarcoma-related translocations. As rare examples ofEWSR1-negative SBRCT have been shown to carry rearrangements forFUSandCICgenes, we undertook a systematic screening for these two genes.CICrearrangements by FISH were detected in 15/22 (68%), while none showed FUS abnormalities. RACE, RT-PCR, and/or long-range DNA PCR performed in two cases with frozen material showed thatCICwas fused to copies of theDUX4gene on either 4q35 or 10q26.3. Subsequent FISH analysis confirmed fused signals ofCICwith either 4q35 or 10q26.3 region in six cases each. Tumors positive forCIC-DUX4fusion occurred mainly in male young adult patients (median age: 29 years), with the extremities being the most frequent location. Microscopically, tumors displayed a primitive, round to oval cell morphology with prominent nucleoli, high mitotic count, and areas of necrosis. O13 expression was variable, being either diffuse or patchy and tumors mostly lacked other markers of differentiation. AlthoughCIC-DUX4resulting in a t(4;19) translocation has been previously described in primitive sarcomas, this is the first report implicating the relatedDUX4on 10q26 in oncogenesis. These results suggest the possibility of a newly defined subgroup of primitive round cell sarcomas characterized byCICrearrangements, distinct from Ewing sarcoma family of tumors.

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