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

Abstract

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.

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

“…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 BCOR gene, or BCL-6 corepressor, is located on the short arm of the X-chromosome and is thought to play a role in regulating gene transcription through epigenetic silencing [7]. As a variant of the polycomb repressive complex 1 (PRC1), BCOR catalyzes histone modification, and has been shown to play a role in stem cell differentiation and function [7].…”

“…The BCOR gene, or BCL-6 corepressor, is located on the short arm of the X-chromosome and is thought to play a role in regulating gene transcription through epigenetic silencing [7]. As a variant of the polycomb repressive complex 1 (PRC1), BCOR catalyzes histone modification, and has been shown to play a role in stem cell differentiation and function [7]. Evidence suggests the BCOR ITD mutation, which occurs most frequently towards C-terminus (exon 15 of 17), affects the functionality of the PUFD (PCGF Ub-like fold discriminator) domain of BCOR and binding of the PRC1 [7].…”

“…Most recently, BCOR internal tandem duplications (ITDs) have been identified as key oncogenic events in pediatric clear cell sarcomas of the kidney (CCSK) [5], primitive myxoid mesenchymal tumor of infancy (PMMTI) [6], undifferentiated round cell sarcoma of infancy [7], and recently, in 4 cases of endometrial stromal sarcomas (ESS) [8, 9]. Some genomic variations in these BCOR ITDs exist; however, the landscape of BCOR ITDs in a large series of cancer cases has not been described.…”

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…Wamstad et al found several functions of BCOR both in vivo and in vitro: (1) in bcor neo mutant mice, which exhibit a parent-of-origin effect (with paternally imprinted X-inactivation), it indicates that Bcor is indispensable in extra-embryonic tissue; (2) loss of Bcor results in delayed repression of pluripotency factor Oct3/4 and delayed activation of genes responsible for ectodermal and mesodermal lineage specification during in vitro differentiation of ES cells; and (3) BCOR is also required for formation of primitive erythrocytes [272] and, in Bcor mutants, there is a failure of heart looping [273]. Mutations of Bcor has been found in acute myeloid leukemia [274], in retinoblastoma [275], in medulloblastoma [276] and in kidney sarcoma [277,278], suggesting its role in tumorigenic processes. Bcor ablation resulted in higher rate of myeloid cell proliferation and differentiation of CRE induced conditional Bcor knockout (Bcor −/Y ) mouse bone marrow cells [279].…”