title: Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas.
abstract: Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose because of overlapping morphologic, immunohistochemical, and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4-related fusions, whereas another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44-year-old man, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by reverse transcription polymerase chain reaction and fluorescence in situ hybridization techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC, and BCOR-CCNB3 abnormalities for BCOR break-apart probes by fluorescence in situ hybridization to detect potential recurrent BCOR gene rearrangements outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, whereas no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3-positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared with classic Ewing's sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SBRCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion-positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs, which presented in young adults, with a variable anatomic distribution. Furthermore, BCOR-rearranged tumors often displayed spindle cell areas, either well defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma.
authors.affiliation: *Department of Pathology, Technische Universität München ¶Children's Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München #Comprehensive Cancer Center Munich (CCCM), Munich, Germany †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Pathology, Brigham and Women's Hospital, Boston, MA §Department of Pathology, UCLA, Los Angeles, CA ∥Department of Pathology, Royal Orthopaedic, Birmingham, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Marisa
authors.initials: M
authors.lastname: Nucci
authors.forename: Sarah
authors.initials: S
authors.lastname: Dry
authors.forename: Sumathi
authors.initials: S
authors.lastname: Vaiyapuri
authors.forename: Gunther H S
authors.initials: GH
authors.lastname: Richter
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018228:Sarcoma, Small Cell / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: C411984:BCOR protein, human; D004268:DNA-Binding Proteins; C471298:MAML3 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C484647:ZC3H7B protein, human