A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion

Abstract

The identification of subtype-specific translocations has revolutionized the diagnostics of sarcoma and has provided new insight into oncogenesis. We used RNA-seq to investigate samples from individuals diagnosed with small round cell tumors of bone, possibly Ewing sarcoma, but which lacked the canonical EWSR1-ETS translocation. A new fusion was observed between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3) on the X chromosome. RNA-seq results were confirmed by RT-PCR and through cloning of the tumor-specific genomic translocation breakpoints. In total, 24 BCOR-CCNB3-positive tumors were identified among a series of 594 sarcoma cases. Gene profiling experiments indicated that BCOR-CCNB3-positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma. Finally, we show that CCNB3 immunohistochemistry is a powerful diagnostic marker for this subgroup of sarcoma and that overexpression of BCOR-CCNB3 or of truncated CCNB3 activates S phase in NIH3T3 cells. Thus, the intrachromosomal X-chromosome fusion described here represents a new subtype of bone sarcoma caused by a newly identified gene fusion mechanism.

Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma

“…23,27 An additional 4-12% of EWSR1-negative round cell sarcomas harbor a recurrent paracentric inversion of chromosome X, leading to gene fusion between BCOR (encoding the BCL6 co-repressor) and CCNB3 (encoding the testis-specific cyclin B3). 15,28 Predominantly arising in the bone in young children, BCOR-CCNB3-associated round cell sarcomas show spindled-to-round cell morphology, with positive immunohistochemistry for CCNB3 in most cases. 15,28,29 Despite histologic overlap with Ewing sarcoma, BCOR-CCNB3 sarcomas do not show an EWSR1-ETS expression signature and thus appear biologically distinct from Ewing sarcoma.…”

“…15,28 Predominantly arising in the bone in young children, BCOR-CCNB3-associated round cell sarcomas show spindled-to-round cell morphology, with positive immunohistochemistry for CCNB3 in most cases. 15,28,29 Despite histologic overlap with Ewing sarcoma, BCOR-CCNB3 sarcomas do not show an EWSR1-ETS expression signature and thus appear biologically distinct from Ewing sarcoma. 15 This is the first study, to our knowledge, that compared NKX2-2 expression in Ewing sarcomas to Ewing sarcoma-like round cell sarcomas with CIC-DUX4 and BCOR-CCNB3 fusions.…”

“…15,28,29 Despite histologic overlap with Ewing sarcoma, BCOR-CCNB3 sarcomas do not show an EWSR1-ETS expression signature and thus appear biologically distinct from Ewing sarcoma. 15 This is the first study, to our knowledge, that compared NKX2-2 expression in Ewing sarcomas to Ewing sarcoma-like round cell sarcomas with CIC-DUX4 and BCOR-CCNB3 fusions. We observed NKX2-2 expression in only 1 of 20 CIC-DUX4 sarcomas and none of 5 BCOR-CCNB3 sarcomas evaluated.…”

“…Of the five BCOR-CCNB3 sarcomas, four were previously confirmed by RT-PCR, with the remaining case confirmed by immunohistochemistry for CCNB3. 15 All 10 poorly differentiated synovial sarcomas were confirmed by FISH for SS18 rearrangement. Genetic confirmation by FISH for EWSR1 gene rearrangement and/or RT-PCR was previously obtained in all angiomatoid fibrous histiocytomas, gastrointestinal clear cell sarcoma-like tumors, and extraskeletal myxoid chondrosarcomas, as well as five clear cell sarcomas and four desmoplastic small round cell tumors.…”

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

“…Till date, two types of intrachromosomal inversions involving the BCOR family have been reported. BCOR-CCNB3 (cyclin B3) fusion was identified by RNASeq in a subtype of bone sarcoma (26). BCOR-CCNB3 fuses exons 1 to 15 of BCOR to exons 5 to 12 of CCNB3 in an inframe manner ( Fig.…”