Bone: Sarcoma with inv(X)(p11.4p11.22) BCOR/CCNB3

2013-03-01   Olivier Delattre , Sarah Cohen-Gogo , Gaëlle Pierron 

1.Institut Curie, Unite de Genetique Somatique - Centre Hospitalier, Paris, France et Unite 830 Institut National de la Sante et la Recherche Medicale (INSERM), Institut Curie - Centre de Recherche, Paris, France (OD); Institut Curie, Unite de Genetique Somatique - Centre Hospitalier, Paris, France (SCG); Unite 830 Institut National de la Sante et la Recherche Medicale (INSERM), Institut Curie - Centre de Recherche, Paris, France (GP)

Summary

Note

BCOR-CCNB3 Ewing-like tumors form a histologically heterogeneous family belonging to the group of small round cell tumors, just as EWS-ETS positive "classical" Ewing.

Clinics and Pathology

Note

Description of this new clinical entity in the literature is recent (Pierron et al., 2012). Clinical data of this small cohort of patients is under current study and only few pieces can be displayed for now.

Epidemiology

BCOR-CCNB3 RT-PCR screening of a series of transcript-negative sarcomas yielded a total of 24 positive cases, out of 594 (4%), meaning this entity is rare among the rare transcript-negative sarcomas.

Clinics

Clinical description is highly similar to that of Ewing sarcoma, with a median age of occurrence of 13 years, a sex ratio desequilibrated towards males, and tumors affecting preferentially long bones, the spine and pelvis. 20% of patients presented with a soft tissue tumor.

Pathology

Pathological reports were consistent with an undifferentiated, small round cell sarcoma, suggestive of the Ewing sarcoma family of tumors. However, in contrast to Ewing sarcoma, approximately half of the cases lacked strong membrane positivity for CD99. BCOR-CCNB3-positive cases that were tested exhibited strong nuclear CCNB3 staining. This finding highlights the potential usefulness of a simple CCNB3 immunohistochemical assay as a diagnostic test for this subgroup of sarcoma.
Atlas Image
Hematoxylin and eosin staining and immunohistochemical analysis of CD99 and CCNB3 in a Ewing case as well as in two BCOR-CCNB3-positive cases. Courtesy Jean-Michel Coindre.

Treatment

Due to the recent description of this entity, retrospective work on received treatment is on-going. Still, the treatment of these tumors is generally based on combined therapy with chemotherapy associated to best local treatment.

Prognosis

Retrospective work on outcome of patients harboring BCOR-CCNB3 positive tumors in on-going. As in all sarcomas, prognosis might be influenced by the presence of metastases at the time of diagnosis.

Cytogenetics

Atlas Image
A paracentric inversion on the X chromosome was seen in FISH experiments. BACs flanking BCOR were labeled with FITC, and BACs flanking CCNB3 were labeled with rhodamine. In control cells, (a lymphoblastoid cell line), the two red spots (or the two green spots) are in close proximity and appear either as a single spot or as unicolor doublets. In BCOR-CCNB3-positive cells with paracentric inversion on the X chromosome, the two red and green spots are split and appear as bicolored doublets.

Cytogenetics morphological

BCOR-CCNB3 Ewing-like tumors show a X-chromosome paracentric inversion; the inversion results in fusion of the complete coding sequence of the BCOR gene to the last 8 exons of CCNB3, leading to a hybrid transcript and an oncogenic chimeric protein.
Atlas Image
Structure of the BCOR-CCNB3 cDNA. The sequence of the BCOR-CCNB3 junction is shown, with the encoded protein sequence reported below it. Red dashed line and arrow indicate the fusion point.

Additional anomalies

SNP6.0 arrays detected no alteration in 11 of the 18 BCOR-CCNB3 Ewing-like cases studied. In the other seven cases, the only recurrent abnormalities were deletions at chromosomes 17p and 10q, each observed in two cases. Neither deletion nor amplification of the fusion partners was observed. Of note, the most frequent copy-number abnormalities of Ewing sarcoma, particularly the gain at chromosome 8 that is observed in ~50% of Ewing sarcoma cases, and the gain of 1q or chromosome 12 or the loss of 16q, which are each observed in ~25% of Ewing sarcoma cases, were not recurrent characteristics of BCOR-CCNB3-positive cases. These data indicate that classic Ewing sarcomas and BCOR-CCNB3-positive tumors do not share common copy-number changes.

Genes Involved and Proteins

Gene name

BCOR (BCL6 corepressor)

Location

Xp11.4

Protein description

interacting co-repressor of BCL6.

Gene name

CCNB3 (cyclin B3)

Location

Xp11.22

Protein description

Cyclin B3, early meiotic cyclin in spermatogenesis.

Result of the chromosomal anomaly

Transcript

The complete coding sequence of the BCOR gene is fused to the last 8 exons of CCNB3, leading to a hybrid transcript and an oncogenic chimeric protein. The stop codon of BCOR (TGA) is included within a putative GGTGAG donor splice-site sequence. Thus, the most likely hypothesis accounting for the fusion mRNA is that this cryptic donor site is spliced with the acceptor site of exon 5 of CCNB3. Splicing was found to be incomplete, leading to both BCOR-CCNB3 and wild-type BCOR expression.

Detection protocole

Sequence should yield a unique and tumor specific PCR product of 290pb.

Description

The full fusion protein is expected to have a molecular weight of 337 kDa and to include the three known ankyrin domains of BCOR as well as the two known cyclin domains of CCNB3.

Oncogenesis

5-bromodeoxyuridine (BrdU) staining of mouse NIH3T3 fibroblasts overexpressing BCOR-CCNB3 or ΔCCNB3, a truncated version of CCNB3 corresponding to the portion involved in the fusion gene, was performed. Compared to the empty vector, both expression vectors led to a twofold increase in the proportion of cells in S phase. Although cell cycle analyses clearly show that the CCNB3 portion of the fusion is potentially sufficient to mediate cell cycle effects, it is expected that oncogenesis also relies on additional phenotypic effects from the full-length fusion protein.

Highly cited references

Pubmed IDYearTitleCitations
223879972012A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion.118
294311832018Transcriptomic definition of molecular subgroups of small round cell sarcomas.62
293001892018BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas.52
242153222014Round cell sarcomas beyond Ewing: emerging entities.42
274287332016BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities.41
265733252015Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney.40
267525462016Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas.39
311502812019BCOR involvement in cancer.36
248058592014BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma.34
253605852015BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children.30
268471752016Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma.28
306339252019New fusion sarcomas: histopathology and clinical significance of selected entities.25
275624942016ETV4 is a useful marker for the diagnosis of CIC-rearranged undifferentiated round-cell sarcomas: a study of 127 cases including mimicking lesions.25
294167162018Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets.24
251764122014Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant.24
288174042017Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion: A Report of 2 Cases Showing Histologic Overlap With Clear Cell Sarcoma of Kidney, Suggesting Further Link Between BCOR-related Sarcomas of the Kidney and Soft Tissues.20
281977242017Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes.20
291040832018Development and Evaluation of a Pan-Sarcoma Fusion Gene Detection Assay Using the NanoString nCounter Platform.19
274435132016Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics.19
288333752018Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion.16
273060602016Ewing sarcoma and the new emerging Ewing-like sarcomas: (CIC and BCOR-rearranged-sarcomas). A systematic review.16
271800562016Defining Ewing and Ewing-like small round cell tumors (SRCT): The need for molecular techniques in their categorization and differential diagnosis. A study of 200 cases.15
272283202016BCOR-CCNB3-positive soft tissue sarcoma with round-cell and spindle-cell histology: a series of four cases highlighting the pitfall of mimicking poorly differentiated synovial sarcoma.14
248016132014Round cell sarcomas - biologically important refinements in subclassification.14
288770602017Clinicopathologic Diversity of Undifferentiated Sarcoma With BCOR-CCNB3 Fusion: Analysis of 11 Cases With a Reappraisal of the Utility of Immunohistochemistry for BCOR and CCNB3.13
256831832015High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: emerging entities of soft tissue tumors with unique histopathologic features--a case report and literature review.12
307094432019Important Recently Characterized Non-Ewing Small Round Cell Tumors.11
320342832020NTRK3 overexpression in undifferentiated sarcomas with YWHAE and BCOR genetic alterations.10
299207352018PAX7 immunohistochemical evaluation of Ewing sarcoma and other small round cell tumours.9
284203192017BCOR-CCNB3 Undifferentiated Sarcoma-Does Immunohistochemistry Help in the Identification?8
316471302020Expanding the clinicopathologic and molecular spectrum of BCOR-associated sarcomas in adults.7
295334642018Genetic analyses of undifferentiated small round cell sarcoma identifies a novel sarcoma subtype with a recurrent CRTC1-SS18 gene fusion.7
260371542015Screening of BCOR-CCNB3 sarcoma using immunohistochemistry for CCNB3: A clinicopathological report of three pediatric cases.7
310330802019Detecting disease-defining gene fusions in unclassified round cell sarcomas using anchored multiplex PCR/targeted RNA next-generation sequencing-Molecular and clinicopathological characterization of 16 cases.6
255346682015[Ewing/PNET sarcoma family of tumors: towards a new paradigm?].6
334882672020Survey of Paediatric Oncologists and Pathologists regarding Their Views and Experiences with Variant Translocations in Ewing and Ewing-Like Sarcoma: A Report of the Children's Oncology Group.5
287591372017Soft tissue sarcomas: From a morphological to a molecular biological approach.5
328406472021Imaging features and clinical course of undifferentiated round cell sarcomas with CIC-DUX4 and BCOR-CCNB3 translocations.4
320486192019Clinicopathologic features of undifferentiated round cell sarcomas of bone & soft tissues: An attempt to unravel the BCOR-CCNB3- & CIC-DUX4-positive sarcomas.4
251059372014Round cell tumors of bone: an update on recent molecular genetic advances.4
306288512019Clear Cell Sarcoma of the Kidney.3
287569812017Congenital undifferentiated sarcoma associated to BCOR-CCNB3 gene fusion.3
329238942020Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant.2
290840552020SATB2 and TLE1 Expression in BCOR-CCNB3 (Ewing-like) Sarcoma, Mimicking Small Cell Osteosarcoma and Poorly Differentiated Synovial Sarcoma.2
300642352018An undifferentiated sarcoma with BCOR-CCNB3 fusion transcript - pathological and clinical retrospective study.2
348193042022Clinicopathologic and molecular analysis of a BCOR-CCNB3 undifferentiated sarcoma of the kidney reveals significant epigenetic alterations.1
318763612020BCOR-CCNB3 fusion-positive clear cell sarcoma of the kidney.1
323644352020Immunophenotype-Genotype Correlations in Clear Cell Sarcoma of Kidney-An Evaluation of Diagnostic Ancillary Studies.1
270678462016[Genetic Aberration and Pathological Diagnosis in Bone and Soft-Tissue Tumors].1
255318592015The small bowel in its hammock: how to avoid irradiation thanks to the sigmoid.1
354430992022Ewing sarcoma and related FET family translocation-associated round cell tumors: A century of clinical and scientific progress.0
355370052022Soft Tissue and Visceral Organ Sarcomas With BCOR Alterations.0
355689492022BCOR-CCNB3 sarcoma with concurrent RNF213-SLC26A11 gene fusion: a rare sarcoma with altered histopathological features after chemotherapy.0
355454652022BCOR-CCNB3 sarcoma arising in the pharynx.0
352516282022BCOR-CCNB3 sarcoma arising in the proximal tibia: A case report.0
358363062022Paediatric BCOR-associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15.0
339095192021BCOR-CCNB3 Sarcoma with Prominent Rhabdoid Cells Mimicking Rhabdomyoblasts: Expanding the Morphologic spectrum of BCOR-CCNB3 Sarcoma.0
342651232021Cytological features of BCOR-CCNB3 sarcoma: Comparison with Ewing sarcoma and synovial sarcoma.0
338884062021BCOR-CCNB3 rearranged sarcoma arising in neck misdiagnosed as thyroid cancer: A case report.0
345152512022Primary Renal BCOR-CCNB3 Fusion Sarcoma: A Case Report and Review of the Literature.0
341030532021Detection of BCOR gene rearrangement in Ewing-like sarcoma: an important diagnostic tool.0
336307012021Meta-analysis of BCOR rearranged sarcomas: challenging the therapeutic approach.0
326484962021Primary Renal Sarcoma With BCOR-CCNB3 Gene Fusion in an 18-Year-Old Male: A Rare Lesion With a Diagnostic Quandary.0
344056082021[Reassessment of EWSR1 gene rearrangement-negative undifferentiated round cell sarcomas in bone and soft tissues by fluorescence in situ hybridization].0
328718372020A Case Series of BCOR Sarcomas With a New Splice Variant of BCOR/CCNB3 Fusion Gene.0
331074962020Erratum: Clinicopathologic features of undifferentiated round cell sarcomas of bone & soft tissues: An attempt to unravel the BCOR-CCNB3- & CIC-DUX4-positive sarcomas.0
316790102020Fine-Needle Aspiration Features of BCOR-CCNB3 Sarcoma.0
316325522019BCOR-CCNB3 fusion and BCOR internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.0
280112562017Erratum to "Undifferentiated round cell sarcoma with BCOR-CCNB3 translocation in the jaw of a child" [2016; Vol 122, No 5, Page e174].0
292271210[What´s new in Ewing-like sarcoma family? Soft tissue and bone sarcomas with CIC/BCOR rearrangement. Review of the literature and first personal experience].0
281736692017[Clinicopathologic analysis of Ewing-like BCOR-CCNB3 undifferentiated sarcoma].0

Bibliography

Pubmed IDLast YearTitleAuthors
223879972012A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion.Pierron G et al

Citation

Olivier Delattre ; Sarah Cohen-Gogo ; Gaëlle Pierron

Bone: Sarcoma with inv(X)(p11.4p11.22) BCOR/CCNB3

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/6411/bone-sarcoma-with-inv(x)(p11-4p11-22)-bcor-ccnb3