Intra‐ and extra‐cranial BCOR‐ITD tumours are separate entities within the BCOR‐rearranged family

Abstract

BCOR‐ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR‐ITD (CNS BCOR‐ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high‐grade endometrial stromal sarcoma, and in the bone and soft tissue as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumour of infancy. Based on a series of 33 retrospective cases, including 10 CNS BCOR‐ITD and 23 BCOR‐ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological, and histopathological findings, and molecular signatures. Whole‐transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. BCOR‐ITD tumours mostly affected young children with a median age at diagnosis of 2.1 years (range 0–62.4). Median overall survival was 3.9 years and progression‐free survival was 1.4 years. This dismal prognosis is shared among tumours in all locations except CCSK. Histopathological review revealed marked differences between CNS BCOR‐ITD and BCOR‐ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n = 22) and DNA methylation (n = 21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single‐cell RNA‐Seq atlases suggests that the distinction between BCOR‐ITD sarcomas and CNS BCOR‐ITD may result from differences in cells of origin.

Outcomes of children with clear cell sarcoma of kidney following NWTS strategies in Shanghai China (2003–2021)

“…Notably, BCOR-ITD tumors constitute an emerging family of aggressive tumors. In addition to CCSK, this family also includes brain tumors, termed central nervous system BCOR-ITD (CNS BCOR-ITD); endometrial tumors, such as high-grade endometrial stromal sarcoma; and bone and soft tissue tumors, such as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumor of infancy [ 31 , 32 ]. In infants, BCOR-ITD tumors often present as locally aggressive tumors in the paraspinal region, and are histologically referred to as primitive myxoid mesenchymal tumor of infancy.…”

Clinical characteristics and outcomes for children, adolescents and young adults with “CIC‐fused” or “BCOR‐rearranged” soft tissue sarcomas: A multi‐institutional European retrospective analysis

“…For the BCOR-ITD tumors no radiological, clinical, nor pathological specificity could be found, except for location in the central nervous system but a common transcriptomic signature with other BCOR rearranged sarcomas. 18 However, all these are described as a distinct entity from ES, and occur in various sites as soft tissue, visceral primaries and less often bone. 3,19 Therapeutic options for such tumors frequently include chemotherapy (CHT) and local surgery with radiotherapy (RT) analogous to treatment of soft tissue sarcomas or ES.…”

“…With location in the kidney, these sarcomas are described as clear cell sarcomas of the kidney (CCSK) 13 . However, these sarcomas are also described as high‐grade endometrial stromal sarcomas (HG‐ESS) 14,15 in bone and soft tissue, referred to as USRCS, but also occurring in infants as primitive mesenchymal myxoid tumor (PMMTI) 16–18 . CIC::DUX4 sarcoma (CDS) or CIC‐rearranged sarcomas seem a rare subcategory of another small round cell sarcoma with histological signs of Ewing sarcoma (ES) 2 .…”

“…In recent analysis, ATXN1 tumors clustered with CIC tumors and YWHAE fused tumors within the BCOR tumors group. For the BCOR‐ITD tumors no radiological, clinical, nor pathological specificity could be found, except for location in the central nervous system but a common transcriptomic signature with other BCOR rearranged sarcomas 18 . However, all these are described as a distinct entity from ES, and occur in various sites as soft tissue, visceral primaries and less often bone 3,19 …”

“… 13 However, these sarcomas are also described as high‐grade endometrial stromal sarcomas (HG‐ESS) 14 , 15 in bone and soft tissue, referred to as USRCS, but also occurring in infants as primitive mesenchymal myxoid tumor (PMMTI). 16 , 17 , 18 CIC::DUX4 sarcoma (CDS) or CIC‐rearranged sarcomas seem a rare subcategory of another small round cell sarcoma with histological signs of Ewing sarcoma (ES). 2 For extracranial sites, “ CIC fused sarcoma” group had biological homology as the “ BCOR rearranged sarcoma” group.…”