title: BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children.
abstract: The BCOR-CCNB3 fusion gene, resulting from a chromosome X paracentric inversion, was recently described in translocation-negative 'Ewing-like' sarcomas arising in bone and soft tissue. Genetic subclassification of undifferentiated unclassified sarcomas may potentially offer markers for reproducible diagnosis and substrates for therapy. Using whole transcriptome paired-end RNA sequencing (RNA-seq) we unexpectedly identified BCOR-CCNB3 fusion transcripts in an undifferentiated spindle-cell sarcoma. RNA-seq results were confirmed through direct RT-PCR of tumor RNA and cloning of the genomic breakpoints from tumor DNA. Five additional undifferentiated sarcomas with BCOR-CCNB3 fusions were identified in a series of 42 pediatric and adult unclassified sarcomas. Genomic breakpoint analysis demonstrated unique breakpoint locations in each case at the DNA level even though the resulting fusion mRNA was identical in all cases. All patients with BCOR-CCNB3 sarcoma were males diagnosed in mid childhood (7-13 years of age). Tumors were equally distributed between axial and extra-axial locations. Five of the six tumors were soft-tissue lesions with either predominant spindle-cell morphology or spindle-cell areas interspersed with ovoid to round cells. CCNB3 immunohistochemistry showed strong nuclear positivity in five tumors before oncologic therapy, but was patchy to negative in post-treatment tumor samples. An RT-PCR assay developed to detect the fusion transcript in archival formalin-fixed tissue was positive in all six cases, with high sensitivity and specificity in both pre- and post-treated samples. This study adds to recent reports on the clinicopathologic spectrum of BCOR-CCNB3 fusion-positive sarcomas, a newly emerging entity within the undifferentiated unclassified sarcoma category and describes a simple RT-PCR assay that in conjunction with CCNB3 immunohistochemistry can be useful in diagnosing these tumors.
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Peters
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Vijetha
authors.initials: V
authors.lastname: Kumar
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sumanth
authors.initials: S
authors.lastname: Polikepahad
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Lin
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Sarabia
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.affiliation: 1] Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Sarcoma Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: HarshaVardhan
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Hsu
authors.initials: H
authors.lastname: Chao
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: 1] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA [3] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M Fatih
authors.initials: MF
authors.lastname: Okcu
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA [3] Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA [4] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA [3] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [4] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA [3] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [4] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: López-Terrada
authors.affiliation: 1] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA [3] Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA [4] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
authors.affiliation: 1] Department of Pathology, Texas Children's Hospital, Houston, TX, USA [2] Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA [3] Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA [4] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Angshumoy
authors.initials: A
authors.lastname: Roy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D019926:Cyclin B / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D050596:Oncogene Fusion / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: C411984:BCOR protein, human; C503694:CCNB3 protein, human; D019926:Cyclin B; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins