title: 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.
authors.affiliation: Institut Curie, Unité de Génétique Somatique-Centre Hospitalier, Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.forename: Carlo
authors.initials: C
authors.lastname: Lucchesi
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Reynaud
authors.forename: Stelly
authors.initials: S
authors.lastname: Ballet
authors.forename: Sarah
authors.initials: S
authors.lastname: Cohen-Gogo
authors.forename: Virginie
authors.initials: V
authors.lastname: Perrin
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics*; D002460:Cell Line; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D019926:Cyclin B / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D050939:Gene Fusion; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D012512:Sarcoma, Ewing / Q000235:genetics; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: C411984:BCOR protein, human; D014408:Biomarkers, Tumor; C503694:CCNB3 protein, human; D019926:Cyclin B; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D034802:RNA-Binding Protein EWS; D012097:Repressor Proteins