Major finding: An X-chromosome paracentric inversion distinguishes a subset of sarcomas.
Mechanism: Ectopic expression of the meiotic cyclin B3 may accelerate proliferation.
Impact: BCOR–CCNB3 tumors are biologically distinct from Ewing sarcomas.
Sarcoma subtypes often express characteristic oncogenic fusion transcripts caused by chromosomal translocations that can facilitate the diagnosis of poorly differentiated tumors. Ewing sarcoma, one of the major types of bone sarcomas in adolescents and young adults, is characterized by EWSR1 and ETS family gene fusions; however, some tumors with clinical and morphologic similarities to Ewing sarcomas lack these canonical fusion transcripts. Pierron and colleagues performed paired-end RNA sequencing on 4 such sarcomas and identified a tumor expressing a fusion of BCL6 corepressor (BCOR) and cyclin B3 (CCNB3), which are nonadjacent genes on the X chromosome. A screen of 594 sarcomas lacking the most common diagnostic fusions revealed that 24 cases harbored the BCOR–CCNB3 fusion, suggesting that this translocation may identify a distinct subset of sarcomas. Most of these tumors were undifferentiated small round-cell sarcomas like Ewing sarcoma, but gene expression profiling and single-nucleotide polymorphism array analysis revealed that these tumors were genetically distinct from Ewing sarcoma and other pediatric cancers. CCNB3 encodes a meiotic cyclin that is only expressed in the testis during spermatogenesis, but BCOR encodes a ubiquitously expressed protein with activity in mesenchymal stem cells, suggesting a possible mechanism whereby ectopic activation of CCNB3 may drive sarcoma progression. Consistent with an oncogenic function of CCNB3, transfection of either BCOR–CCNB3 or the fused segment of CCNB3 into NIH3T3 cells doubled the number of cells in S phase. Finally, as only BCOR–CCNB3-positive tumors stained strongly for CCNB3, this sarcoma subtype may not only have a unique biology but may also be amenable to a simple immunohistochemistry-based diagnostic test.
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