maureen o’sullivan 1,2 *, tony ng 1 *, torsten nielsen 1, malcolm hayes 1,3, paul clarkson 4,...
TRANSCRIPT
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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
Novel translocation t(2;16)(q35;p11) producing an in-frame fusion of FUS and FEV in a Ewing
sarcoma lacking EWS rearrangement
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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.
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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.
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Pathology
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Cytogenetics
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t(2;16)(q35;p11)
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FISH with FUS Break-apart Probe
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FISH with BAC RP11-207M4
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RT-PCR, Cloning and Sequencing
• Primers : Forward - FUS exon 1; Reverse - FEV exon 3
• Product of 1.4Kb on electrophoresis
• Cloned and sequenced
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RT-PCR, cloning and sequencing
FEV Exon 2 FUS Exon 10
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In-frame FUS exon 10 to FEV exon 2 fusion
• Novel Translocation
• Another example of a translocation in EFT involving FUS
• New FUS breakpoint
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FUS, FEV Breakpoints – modified from Janknecht; Gene 2005
EWS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
SYQG activation domain RGG-rich RNA-binding RGG-rich Zn RGG-rich
FUS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
SYQG activation domain RGG-rich RNA-binding RGG Zn RGG-rich
FUS-FEV
FEV
1 2 3
DNA-binding Ala-rich
FLI-1 1 2 3 4 5 6 7 8 9
Pointed domain DNA-binding Pro-rich
ERG
Pointed domain DNA-binding Pro-rich
ETV1
AD DNA-binding Pro-rich
ETV4
AD DNA-binding Pro-rich
1 2 3 4 5 6 7 8 9 10 2 3
SYQG activation domain RGG-rich RNA-binding DNA-binding Ala-rich
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?Further Evidence of FUS or FEV rearrangement in EFTs? – TMAs being
evaluated
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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
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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