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New Sarcoma Defined by BCOR-CCNB3 Fusion

New Sarcoma Defined by BCOR-CCNB3 Fusion. Laila Moharram , Hussam Haddad King Hussein Cancer Center. Case History. 13 year old male Left pelvic mass. Pediatric Round cell Sarcomas. Rhabomyosarcoma Ewing sarcoma/PNET Neuroblastoma Lymphoma/ leukemia Small cell osteosarcoma

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New Sarcoma Defined by BCOR-CCNB3 Fusion

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  1. New Sarcoma Defined by BCOR-CCNB3 Fusion LailaMoharram, Hussam Haddad King Hussein Cancer Center

  2. Case History • 13 year old male • Left pelvic mass

  3. Pediatric Round cell Sarcomas • Rhabomyosarcoma • Ewing sarcoma/PNET • Neuroblastoma • Lymphoma/ leukemia • Small cell osteosarcoma • Mesenchymalchondrosarcoma • Sclerosing RMS • BRD/NUT carcinoma • Extrarenalrhabdoid tumor • Desmoplastic small round cell tumor • Undifferentiated sarcoma

  4. CD99 PAS

  5. Desmin Myogenin

  6. BAF47 BCL-2

  7. Immunostains Positive CD99 (Weak) BCL-2 CD56 Negative synaptophysin desmin, myogenin S100 protein CD31 EMA and CK-MNF FLI-1

  8. EWSR1 Fusion Partners • FLI1(85%) • ERG(5-10%) • FEV • ETV1 • E1Af EWSR1-ETS

  9. Working Diagnosis Small round blue cell tumor of the bone FISH is negative for EWSR1 rearrangement

  10. EWSR1 fusion negative Ewing sarcoma • Rare • FUS FISH • FUS-ERG or FUS-FEV

  11. Diagnosis? DX: Undifferentiated spindle and round cell sarcoma.

  12. Undifferentiated sarcoma • Fusion negative Ewing-like neoplasms • CD99: Positive, focal or negative. • Proportion of cases shows new fusion CIC-DUX4 • t(4;19) • t(10;19)

  13. Consultation CIC-DUX4 gene fusion negative The tumor instead showed BCOR-CCNB3fusion.

  14. Fusion-specific RT-PCR to screen a series of 594 sarcomas. • 24 BCOR-CCNB3–positive tumors were identified

  15. Gene profiling experiments indicated that BCOR-CCNB3–positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma.

  16. BCOR-CCNB3 Sarcoma • Clinical description is similar to Ewing Sarcoma. • Median age 13 years • Male predominance • Preferentially long bones, the spine and pelvis. • 20%: soft tissue tumor.

  17. Pathology • Undifferentiated, small round cell sarcoma, suggestive of the Ewing sarcoma. • Half lacked strong membrane positivity for CD99.

  18. BCOR and CCNB3 Genes • Both on the X chromosome • BCORencodes ubiquitous transcriptional repressor that associates with BCL6 oncoprotein • CCNB3expression is tightly restricted to thetestis, with CCNB3 encoding an early meiotic cyclin .

  19. Ectopic expression of CCNB3 as a result of the BCOR gene fusion may constitute a key oncogenic event.

  20. Undifferentiated/ unclassifed Sarcomas • Introduced a chapter on undifferentiated sarcomas. • No reproducible immunophenotype. • Patchy CD99 • CD34+-: No discriminatory value. • EM: No evidence of differentiation.

  21. Ewing or Ewing look-alike? Undifferentiated Sarcoma BCOR-CCNB3 sarcoma CIC-DUX4 sarcoma?

  22. References • Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre J-M, Antonescu CR. High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1- negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 2012;51:207-218. • Pierron G et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Gen 2012; 44: 461-466. • Barr FG, Womer RB. Molecular diagnosis of Ewing family tumors too many fusions...? Journal of Molecular Diagnostics.2007;9(4):437–440. • Shing DC, McMullan DJ, Roberts P et al. FUS/ERG gene fusions in Ewing’s tumors. Cancer Res 2003;63:4568–4576. • French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, et al. Midline carcinoma of children and young adults with NUT rearrangement. J ClinOncol. 2004;22(20):4135–4139.

  23. References • Ng TL, O’Sullivan MJ, Pallen CJ, Hayes M, Clarkson PW, Winstanley M, Sorensen PH, Nielsen TO, Horsman DE. Ewing sarcoma with novel translocation t(2;16) producing an in-frame fusion of FUS and FEV. J Mol Diagn. 2007;9:459–463. • Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H, Mukai H, Gotoh T, Motoi T, Fukayama M, Aburatani H, Takizawa T, Nakamura T. Fusion between CIC and DUX4 up- regulates PEA3 family genes in Ewing-like sarcomas with t (4;19)(q35;q13) translocation. Hum Mol Genet 2006;15:2125- 2137 • Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A. Molecular diagnosis of Ewing sarcoma/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors. Modern Pathology. 2006;19(1):1–8.

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