A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma

Abstract

Congenital (or infantile) fibrosarcoma (CFS) is a malignant tumour of f ibroblasts that occurs in patients aged two years or younger. CFS is unique among human sarcomas in that it has an excellent prognosis and very low metastatic rate1,2. CFS is histologi-cally identical to adult-type f ibrosarcoma (ATFS); however, ATFS is an aggressive malignancy of adults and older children that has a poor prognosis3. We report a novel recurrent t(12;15)(p13;q25) rearrangement in CFS that may underlie the distinctive biological properties of this tumour. By cloning the chromosome breakpoints, we show that the rearrangement fuses the ETV6 (also known as TEL) gene from 12p13 with the 15q25 NTRK3 neurotrophin-3 receptor gene (also known as TRKQ. Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed. These were not detected in ATFS or infantile fibromatosis (IFB), a histologically similar but benign fibroblastic proliferation occurring in the same age-group as CFS. ETV6-NTRK3 fusion transcripts encode the helix-loop-helix (HLH) protein dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to onco-genesis by dysregulation of NTRK3 signal transduction pathways. Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Fisher, C. Fibromatosis and fibrosarcoma in infancy and childhood. Eur. J. Cancer 32A, 2094–2100 (1996).

    CAS  Article  Google Scholar 

  2. 2

    Pizzo, P.A. & Poplack, D.G. Principles and Practice ofPediatric Oncology 1–1350 (J.B. Lippincott, Philadelphia, 1997).

  3. 3

    Enzinger, F.M. & Weiss, S.W. Soft Tissue Tumors 1–1120 (C.V. Mosby, St. Louis, 1995).

  4. 4

    Speleman, F. et al. Cytogenetic investigation of a case of congenital fibrosarcoma. Cancer Genet Cytogenet. 39, 21–24 (1989).

    CAS  Article  Google Scholar 

  5. 5

    Mandahl, N., Helm, S., Rydholm, A., Willen, H. & Mitelman, F. Nonrandom numerical chromosome aberations (+8, +11, +17, +20) in infantile fibrosarcoma. Cancer Genet. Cytogenet. 40, 137–138 (1989).

    CAS  Article  Google Scholar 

  6. 6

    Schofield, D.E., Fletcher, J.A., Grier, H.E. & Yunis, E.J. Fibrosarcoma in infants and children. Application of new techniques. Am. J. Surg. Pathol. 18, 14–24 (1994).

    CAS  Article  Google Scholar 

  7. 7

    Golub, T.R., Barker, G.F., Lovett, M. & Gilliland, D.G. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77, 307–16 (1994).

    CAS  Article  Google Scholar 

  8. 8

    Buijs, A. et al. Translocation (12;22) (p13;q11) in myeloproliferative disorders results in fusion of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. Oncogene 10,1511–1519 (1995).

    CAS  PubMed  Google Scholar 

  9. 9

    Golub, T.R. et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 92, 4917–4921 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Papadopoulos, P., Ridge, S.A., Boucher, C.A., Stocking, C. & Wiedemann, L.M. The novel activation ABL by fusion to an ets-related gene, TEL. Cancer Res. 55, 34–38 (1995).

    CAS  PubMed  Google Scholar 

  11. 11

    Peeters, P. et al. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood 90, 2535–2540 (1997).

    CAS  PubMed  Google Scholar 

  12. 12

    Baens, M., Peeters, P., Guo, C., Aerssens, J. & Marynen, P. Genomic organization of TEL: the human ETS-variant gene 6. Genome Res. 6, 404–413 (1996).

    CAS  Article  Google Scholar 

  13. 13

    Frohman, M.A., Dush, M.K. & Martin, G.R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natl. Acad. Soc. USA 85, 8998–9002 (1988).

    CAS  Article  Google Scholar 

  14. 14

    Lamballe, F., Klein, R. & Barbacid, M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66 (1991).

    CAS  Article  Google Scholar 

  15. 15

    McGregor, L.M., Baylin, S.B., Griffin, C.A., Hawkins, A.L. & Nelkin, B.D. Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant. Genomics 22, 267–272 (1994).

    CAS  Article  Google Scholar 

  16. 16

    Lemmon, M.A. & Schlessinger, J. Regulation of signal transduction and signal diversity by receptor oligomerization. Trends Biochem. Sci. 19, 459–463 (1994).

    CAS  Article  Google Scholar 

  17. 17

    Barbacid, M., Trk family of neurotrophin receptors. J. Neurobiology 25, 1386–1403 (1994).

    CAS  Article  Google Scholar 

  18. 18

    Shelton, D.L. et al. Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J. Neurosci. 15, 477–491 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Bonin, G., Scamps, C., Turc-Carel, C. & Lipinski, M. Chimeric EWS/FLI1 transcript in a Ewing cell line with a complex t(11;22;14) translocation. Cancer Res. 53, 3655–3657 (1993).

    CAS  PubMed  Google Scholar 

  20. 20

    Desmaze, C. et al. Multiple chromosomal mechanisms generate an EWS/FLM or an EWS/ERG fusion gene in Ewing tumors. Cancer Genet. Cytogenet. 97, 12–19 (1997).

    CAS  Article  Google Scholar 

  21. 21

    Uphoff, C.C. et al. Occurence of TEL-AML1 fusion resulting from (12;21) translocation in human early B-lineage leukemia cell lines. Leukemia 11, 441–447 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Raynaud, S. et al. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 87, 2891–2899 (1996).

    CAS  PubMed  Google Scholar 

  23. 23

    Sorensen, P.H.B. et al. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nature Genet. 6, 146–151 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Ichikawa, H., Shimizu, K., Hayashi, Y. & Ohki, M., An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res. 54, 2865–2868 (1994).

    CAS  Google Scholar 

  25. 25

    Verma, R.S. & Babu, A. Human chromosomes: manual of basic techniques. (Pergamon Press, New York, 1989).

  26. 26

    Dracopoli, N.C. Current Protocols in Human Genetics (John Wiley and Sons, Inc., New York, 1996).

  27. 27

    Sorensen, P.H.B. et al. Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma. Proc. Natl. Acad. Sci. USA 93, 1038–1043 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Sorensen, P.H.B. et al. Reverse Transcriptase PCR Amplification of EWS/Fli-1 Fusion Transcripts as a Diagnostic Test for Peripheral Primitive Neuroectodermal Tumors of Childhood. Diag. Mol. Pathol. 2, 147–157 (1993).

    CAS  Article  Google Scholar 

  29. 29

    Sambrook, J., Fritch, E.F. & Maniatis, T. Molecular cloning: a laboratory manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

  30. 30

    Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Poul H.B. Sorensen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Knezevich, S., McFadden, D., Tao, W. et al. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18, 184–187 (1998). https://doi.org/10.1038/ng0298-184

Download citation

Further reading