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BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities

Kao, Yu-Chien MD; Sung, Yun-Shao MSc; Zhang, Lei MD; Jungbluth, Achim A. MD; Huang, Shih-Chiang MD; Argani, Pedram MD; Agaram, Narasimhan P. MBBS; Zin, Angelica PhD; Alaggio, Rita MD; Antonescu, Cristina R. MD

The American Journal of Surgical Pathology: December 2016 - Volume 40 - Issue 12 - p 1670–1678
doi: 10.1097/PAS.0000000000000697
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With the advent of next-generation sequencing, an increasing number of novel gene fusions and other abnormalities have emerged recently in the spectrum of EWSR1-negative small blue round cell tumors (SBRCTs). In this regard, a subset of SBRCTs harboring either BCOR gene fusions (BCOR-CCNB3, BCOR-MAML3), BCOR internal tandem duplications (ITD), or YWHAE-NUTM2B share a transcriptional signature including high BCOR mRNA expression, as well as similar histologic features. Furthermore, other tumors such as clear cell sarcoma of kidney (CCSK) and primitive myxoid mesenchymal tumor of infancy also demonstrate BCOR ITDs and high BCOR gene expression. The molecular diagnosis of these various BCOR genetic alterations requires an elaborate methodology including custom BAC fluorescence in situ hybridization (FISH) probes and reverse transcription polymerase chain reaction assays. As these tumors show high level of BCOR overexpression regardless of the genetic mechanism involved, either conventional gene fusion or ITD, we sought to investigate the performance of an anti-BCOR monoclonal antibody clone C-10 (sc-514576) as an immunohistochemical marker for sarcomas with BCOR gene abnormalities. Thus we assessed the BCOR expression in a pathologically and genetically well-characterized cohort of 25 SBRCTs, spanning various BCOR-related fusions and ITDs and YWHAE-NUTM2B fusion. In addition, we included related pathologic entities such as 8 CCSKs and other sarcomas with BCOR gene fusions. As a control group we included 20 SBRCTs with various (non-BCOR) genetic abnormalities, 10 fusion-negative SBRCTs, 74 synovial sarcomas, 29 rhabdomyosarcomas, and other sarcoma types. In addition, we evaluated the same study group for SATB2 immunoreactivity, as these tumors also showed SATB2 mRNA upregulation. All SBRCTs with BCOR-MAML3 and BCOR-CCNB3 fusions, as well as most with BCOR ITD (93%), and all CCSKs showed strong and diffuse nuclear BCOR immunoreactivity. Furthermore, all SBRCTs with YWHAE-NUTM2B also were positive. SATB2 stain was also positive in tumors with YWHAE-NUTM2B, BCOR-MAML3, BCOR ITD (75%), BCOR-CCNB3 (71%), and a subset of CCSKs (33%). In conclusion, BCOR immunohistochemical stain is a highly sensitive marker for SBRCTs and CCSKs with BCOR abnormalities and YWHAE-rearrangements and can be used as a useful diagnostic marker in these various molecular subsets. SATB2 immunoreactivity is also present in the majority of this group of tumors.

*Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY

§Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

Institute of Pediatric Research Citta’della Speranza

Department of Medical and Diagnostic Sciences and Special Therapies, Pathology Unit, University of Padua, Padua, Italy

Conflicts of Interest and Source of Funding: Supported in part by: P50 CA140146-01 (C.R.A.); P30-CA008748 (C.R.A.); Kristen Ann Carr Foundation (C.R.A.); Cycle for survival (C.R.A.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Cristina R. Antonescu, MD, Pathology Department, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (e-mail: antonesc@mskcc.org).

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