Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas

Abstract

Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose due to overlapping morphologic, immunohistochemical and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4 related fusions, while another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44 year-old male, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by RT-PCR and FISH techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC and BCOR-CCNB3 abnormalities, for BCOR break-apart probes by FISH to detect potential recurrent BCOR gene rearrangements, outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, while no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3 positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared to classic Ewing sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SRBCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs which presented in young adults, with a variable anatomic distribution. Furthermore BCOR-rearranged tumors often displayed spindle cell areas, either well-defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma.

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

“…To further investigate the distribution of these genetic abnormalities among URCS of different age groups and across different tumor entities prevalent in young children, we also included as controls: 14 cases of non-infantile URCS, 2 Ewing sarcomas, 3 CIC-DUX4 positive round cell sarcomas, 3 BCOR - CCNB3 positive round cell sarcomas, 1 BCOR - MAML3 round cell sarcoma, 11 8 rhabdomyosarcomas (3 embryonal rhabdomyosarcoma, 5 spindle cell/sclerosing rhabdomyosarcoma), 2 malignant ectomesenchymomas, and 1 myofibromatosis. Four CCSK were included as positive controls.…”

Epigenetic Alterations in Bone and Soft Tissue Tumors

“…Since the identification of BCOR-CCNB3 fusions, other BCOR fusions have been reported in undifferentiated round cell sarcomas occurring in older, predominantly male patients, including BCOR-MAML3 and ZC3H7B-BCOR fusions. 66 …”

Head and Neck Round Cell Sarcomas: A Comparative Clinicopathologic Analysis of 2 Molecular Subsets: Ewing and CIC-Rearranged Sarcomas

“…The 2-year overall survival (OS) rate for HN-CRS patients was 78%, while for HN-ES it was 100%. The OS of ES and CRS showed a trend toward a favorable and BCOR-related fusions involving CCNB3, MAML3, and ZC3H7B gene partners [11][12][13][14][15][16][17][18]. As most of the initial series have included a limited number of cases of each molecular subset, definitive classification of these tumors within or outside the more common ES spectrum has been difficult to establish.…”