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

Abstract

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 (PMMTI) 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 FISH probes and RT-PCR 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 SBRCT with various (non-BCOR) genetic abnormalities, 10 fusion-negative SBRCT, 74 synovial sarcomas, 29 rhabdomyosarcoma and other sarcoma types. Additionally we evaluated the same study group for SATB2 immunoreactivity, as these tumors also showed SATB2 mRNA up-regulation. 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.

A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

“…The BCOR ITD event occurred most frequently in exon 15, 69.7% (23/33), at the C-terminus of the gene, supporting previous lines of evidence (Fig. 1; other exons, see Table 1) [2, 5-9]. The mean length of the exon 15 duplication events in exon 15 was 31.7 codons in length (range 30–38 codons; Table 1).…”

“…In addition, BCOR can also be frequently overexpressed in high-grade ESS harboring YWHAE- NUT2B rearrangements via an unknown mechanism [2, 5-7, 9]. In addition, it has been recently demonstrated that BCOR ITD is a notable mechanism for BCOR overexpression in three high-grade uterine sarcoma cases regarded as high-grade ESS that did not harbor a characteristic ESS gene fusion [9].…”

“…The presence of BCOR ITDs has previously been described as key oncogenic driver events in CCSK, PMMTI, round cell sarcoma of infancy, and recently, several index cases of ESS [2-6]. We retrospectively searched 140,411 advanced cancer cases that had undergone CGP in the course of clinical care to identify the frequency, spectrum, and disease landscape of BCOR ITDs across cancer.…”

“…The X-linked BCOR gene ( BCL-6 Corepressor) is a member of the PRC1 complex and potentiates transcriptional repression through BCL6 binding of PRC1. Additionally, BCOR may independently influence gene expression through class I and II histone deacetylase interaction [2-4]. As such, alterations of BCOR have been linked to tumors of mesenchymal origin, often as a result of BCOR gene fusions (i.e., BCOR-CCNB3 , BCOR-MAML3 ) in small round blue cell tumors [2].…”

Role of Next-Generation Sequencing as a Diagnostic Tool for the Evaluation of Bone and Soft-Tissue Tumors

“…These tumors also contain tumor cells with vesicular nuclei, with distinct, often enlarged nucleoli, but lacking a higher degree of heterogeneity, which is typical for other tumors in the ES family [33] . IHC may facilitate the diagnosis of ELS, e.g., WT1 positivity in CIC-DUX4-associated sarcomas [33][34][35] or CCNB3 or BCOR staining to distinguish BCOR-CCNB3-associated sarcomas from other ELS [36,37] . Further specific immunostaining to differentiate SBRCT is listed in Table 2 .…”