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• Mesenchymal

chondrosarcoma

• Sclerosing RMS• BRD/NUT carcinoma• Extrarenal rhabdoid

tumor• Desmoplastic small

round cell tumor• Undifferentiated

sarcoma

CD99 PAS

Myogenin Desmin

BAF47 BCL-2

Immunostains

PositiveCD99 (Weak)BCL-2CD56

Negativesynaptophysin desmin, myogeninS100 protein CD31EMA and CK-MNFFLI-1

EWSR1 Fusion Partners

• FLI1 (85%)• ERG (5-10%)• FEV• ETV1• E1Af

EWSR1-ETS

Working Diagnosis

Small round blue cell tumor of the bone• FISH is negative for EWSR1 rearrangement

EWSR1 fusion negative Ewing sarcoma

• Rare• FUS FISH• FUS-ERG or FUS-FEV

Diagnosis?

DX:

Undifferentiated spindle and round cell sarcoma.

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)

Consultation

CIC-DUX4 gene fusion negative

The tumor instead showed BCOR-CCNB3 fusion.

• Fusion-specific RT-PCR to screen a series of 594 sarcomas.

• 24 BCOR-CCNB3–positive tumors were identified

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

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.

Pathology

• Undifferentiated, small round cell sarcoma, suggestive of the Ewing sarcoma.

• Half lacked strong membrane positivity for CD99.

BCOR and CCNB3 Genes

• Both on the X chromosome• BCOR encodes ubiquitous transcriptional

repressor that associates with BCL6 oncoprotein

• CCNB3 expression is tightly restricted to the testis, with CCNB3 encoding an early meiotic cyclin .

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

Undifferentiated/ unclassifed Sarcomas

• Introduced a chapter on undifferentiated sarcomas.

• No reproducible immunophenotype.• Patchy CD99 • CD34+-: No discriminatory value.• EM: No evidence of differentiation.

Ewing or Ewing look-alike?

Undifferentiated Sarcoma

CIC-DUX4 sarcoma? BCOR-CCNB3 sarcoma

References 1. 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.

2. Pierron G et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Gen 2012; 44: 461-466.

3. Barr FG, Womer RB. Molecular diagnosis of Ewing family tumors too many fusions...? Journal of Molecular Diagnostics.2007;9(4):437–440.

4. Shing DC, McMullan DJ, Roberts P et al. FUS/ERG gene fusions in Ewing’s tumors. Cancer Res 2003;63:4568–4576.

5. 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 Clin Oncol. 2004;22(20):4135–4139.

References 6. 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.

7. 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

8. 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.