BCOR-CCNB3 (Ewing-like) Sarcoma

Sung

et al. 2016

171

207

Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogeneous group of tumors, often lacking known genetic abnormalities. Based on a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSK are characterized by BCOR exon 16 internal tandem duplications (ITD), while a smaller subset shows YWHAE-NUTM2B/E fusions. Due to overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCS and 7 PMMTI selected, RNA sequencing (RNAseq) was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by FISH or RT-PCR, and BCOR ITD by PCR. A control group of 4 CCSK, 14 URCS in older children or adults without known gene fusion, and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE-NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, while lacking BCOR ITD. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl from the back. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITD, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures and varying degree of myxoid change were occasionally seen. BCOR ITD positive tumors occurred preferentially in the somatic soft tissue of trunk, abdomen and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared to other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features and genetic signature; thus raising the possibility of a soft tissue counterpart to CCSK.

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 88%

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy

Sung

et al. 2016

171

207

“…BCOR-CCNB3 sarcomas of bone and soft tissues were initially recognized as a subset of EWS -non-rearranged “Ewing sarcomas”, and have historically been treated with Ewing sarcoma chemotherapy regimens, though some evidence exists that their behavior may be more indolent 17 . As such, BCOR-CCNB3 sarcomas are typically treated as Ewing sarcomas at most centers today.…”

Section: Discussionmentioning

confidence: 99%

“…Second, a BCOR-CCNB3 gene fusion resulting from an X chromosomal pericentric inversion has been identified in previously unclassified soft tissue and bone sarcomas which typically affect teenagers and young adults with a male predominance 15–18 . While the majority of these BCOR-CCNB3 sarcomas were identified among EWSR1 -negative Ewing-sarcomas and thought to be primarily small round neoplasms 15, 16 , more recently cases with spindled morphology have been described 17, 18 . Importantly, high levels BCOR mRNA expression resulting in BCOR protein overexpression as detected by immunohistochemistry 5 and a distinctive BCOR -driven transcriptional profile 14 have been identified in URCS/PMMTI, BCOR-CCNB3 fusion-positive sarcomas, and CCSK, suggesting that all of these neoplasms are highly genetically related.…”

Section: Introductionmentioning

confidence: 99%

Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion

Argani¹,

et al. 2017

We report two primary renal sarcomas demonstrating BCOR-CCNB3 gene fusions that have recently been identified in undifferentiated round cell sarcomas of bone and soft tissue. These neoplasms occurred in male children aged 11 and 12, and both were cystic as a result of entrapment and dilatation of native renal tubules. Both cases were composed of variably cellular bland spindle cells with fine chromatin set in myxoid stroma and separated by a branching capillary vasculature. Both neoplasms demonstrated immunoreactivity for BCOR, cyclin D1, TLE1 and SATB2 in the spindle neoplastic cells and negativity in the prominent capillary vasculature. One case was extensively cystic and had hypocellular areas that simulated cystic nephroma; this neoplasm recurred 3 years later as a solid, highly cellular spindle cell sarcoma in the abdominal cavity. The morphology and immunoprofile of these renal neoplasms was compared to a control group of other sarcomas with BCOR genetic abnormalities, including clear cell sarcoma of the kidney (CCSK), infantile undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy (URCS/PMMTI), and bone/soft tissue sarcomas with BCOR-CCNB3 gene fusion; along with primary renal synovial sarcoma. Our findings show that the renal sarcomas with BCOR-CCNB3 gene fusion overlap with CCSK. They are in keeping with a “BCOR-alteration family” of renal and extra-renal neoplasms which includes CCSK and URCS/PMMTI (which typically harbor BCOR internal tandem duplication), and BCOR-CCNB3 sarcomas, all of which are primarily driven by BCOR overexpression and have overlapping (but not identical) clinicopathologic features.

“…Two such examples include the consistent nuclear expression of WT1 in CIC-DUX4 positive small blue round cell tumors (SBRCTs) 7 and the CCNB3 nuclear overexpression in BCOR-CCNB3 positive tumors. 4,8,9 Although most SBRCTs harboring either BCOR genetic abnormalities or YWHAE fusions show significant BCOR mRNA up-regulation, 6,10,11 no BCOR immunohistochemical marker has been investigated to date in this molecular subset of tumors. BCOR protein expression has been demonstrated by immunoblotting and immunohistochemistry in a small number of CCSKs.…”

Section: Introductionmentioning

confidence: 99%

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

Sung

et al. 2016

183

161

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.