Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas
- 1 April 2016
- journal article
- case report
- Published by Ovid Technologies (Wolters Kluwer Health) in The American Journal of Surgical Pathology
- Vol. 40 (4), 433-442
- https://doi.org/10.1097/pas.0000000000000591
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.Keywords
This publication has 39 references indexed in Scilit:
- Gene set enrichment analysis of RNA-Seq data: integrating differential expression and splicingBMC Bioinformatics, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusionNature Genetics, 2012
- High prevalence of CIC fusion with double‐homeobox (DUX4) transcription factors in EWSR1‐negative undifferentiated small blue round cell sarcomasGenes, Chromosomes and Cancer, 2011
- Promiscuous partnerships in Ewing's sarcomaCancer Genetics, 2011
- RSEQtools: a modular framework to analyze RNA-Seq data using compact, anonymized data summariesBioinformatics, 2010
- BCOR regulates mesenchymal stem cell function by epigenetic mechanismsNature, 2009
- EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiationProceedings of the National Academy of Sciences of the United States of America, 2009
- A large genome center's improvements to the Illumina sequencing systemNature Methods, 2008
- Polycomb Group and SCF Ubiquitin Ligases Are Found in a Novel BCOR Complex That Is Recruited to BCL6 TargetsMolecular and Cellular Biology, 2006