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Molecular Pathology of Ewing Family Tumours

Novel translocation t(2;16)(q35;p11) producing an in-frame fusion of FUS and FEV in a Ewing sarcoma lacking EWS rearrangement. Maureen O’Sullivan 1,2 *, Tony Ng 1 *, Torsten Nielsen 1 , Malcolm Hayes 1,3 , Paul Clarkson 4 , Catherine Pallen 5 , Poul Sorensen 1,6 , Doug Horsman 1,3

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Molecular Pathology of Ewing Family Tumours

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  1. Novel translocation t(2;16)(q35;p11) producing an in-frame fusion of FUS and FEV in a Ewing sarcomalacking EWS rearrangement Maureen O’Sullivan1,2 *, Tony Ng1 *, Torsten Nielsen1, Malcolm Hayes1,3, Paul Clarkson4, Catherine Pallen5, Poul Sorensen1,6, Doug Horsman1,3 1 Department of Pathology and Laboratory Medicine, University of British Columbia, 2 Division of Anatomic Pathology, British Columbia’s Children’s Hospital, 3 Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, 4 Department of Surgery, UBC 5 Department of Pediatrics, Child and Family Research Institute, UBC, 6 Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada *These authors contributed equally

  2. Molecular Pathology of Ewing Family Tumours • Ancillary diagnostic and potentially prognostic value • Typically, EWS (member of TET family) rearranged with any one of a number of Ets family members: Fli1, Erg, ETV1, ETV4, FEV. • Recent report of additional TET family member FUS rearranged with Erg in 4 cases of EFT.

  3. Case History • 33 year-old man sustains pathologic fracture while snowboarding • Plain film images show moth-eaten distal clavicle • Incisional biopsy inadequate, but with suspicious population of small blue cells • Excisional biopsy = EFT • Patient treated with 11 courses of chemo, irradiation and then surgical excision = negative margins and 100% tumour kill.

  4. Pathology

  5. Cytogenetics

  6. t(2;16)(q35;p11)

  7. FISH with FUS Break-apart Probe

  8. FISH with BAC RP11-207M4

  9. RT-PCR, Cloning and Sequencing • Primers : Forward - FUS exon 1; Reverse - FEV exon 3 • Product of 1.4Kb on electrophoresis • Cloned and sequenced

  10. RT-PCR, cloning and sequencing FEV Exon 2 FUS Exon 10

  11. In-frame FUS exon 10 to FEV exon 2 fusion • Novel Translocation • Another example of a translocation in EFT involving FUS • New FUS breakpoint

  12. FUS, FEV Breakpoints – modified from Janknecht; Gene 2005

  13. ?Further Evidence of FUS or FEV rearrangement in EFTs? – TMAs being evaluated

  14. Conclusion • Novel Chromosomal Translocation t(2;16)(q35;p11) in Ewing sarcoma; • Underscores the interchangeability of fusion partners in EFT translocations • Consider FISH with FUS break-apart if EWS break-apart negative

  15. 3 weekly cycles, 11 in total, alternating 6 cycles of ifosfamide 9g/m2 etoposide 500mg/m2 given over 5 days with 5 cycles of vincristine 2mg, doxorubicin 75mg/m2, cyclophosphamide 1g/m2 given on 1 day local control commenced after 5 cycles with radiation, 45 Gy in 25 fractions (chemotherapy continued concurrently) then 8 weeks post radiation surgery with resection of distal clavicle and surrounding tissues

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