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Molecular characterization of pediatric spindle cell tumors Knezevich, Stevan Robert


Congenital fibrosarcoma (CFS) is a cellular, mitotically active neoplasm of soft tissues. It affects infants less than two years of age, has a low metastatic rate and a relatively high propensity for local recurrence. One of the predominant clinical issues surrounding CFS is its distinction from other histologically identical and virtually indistinguishable pediatric spindle cell tumors including adult-type fibrosarcoma (ATFS) and infantile fibromatosis (IFB). ATFS is a malignant lesion that is treated more aggressively than CFS, while IFB is a benign lesion which is treated less aggressively. Reliable distinction between these entities is therefore clinically very important. We therefore wanted to identify a diagnostic tool to distinguish CFS from other fibroblastic tumors such as ATFS and IFB. Cytogenetic analysis of CFS cases has shown a nonrandom gain in chromosomes 8, 11, 17, and 20 with trisomy for chromosome 11 being present in most cases. Cytogeneticists at the Department of Pathology of B.C.C.H. recently identified recurrent cytogenetic alterations involving chromosome 12pl3 and 15q25 in three CFS cases, which were not present in ATFS, IFB, and aggressive fibromatosis. Cloning of the chromosomal breakpoints revealed a novel fusion between the ETS transcription factor member, ETV6, and the gene encoding the neurotrophin-3 cell surface receptor, NTRK3. This fusion results in the juxtaposition of the HLH dimerization domain of ETV6 to the protein tyrosine kinase (PTK) domain of NTRK3. We hypothesized that this molecule acts as an aberrant PTK signaling molecule in which the HLH domain mediates ligand independent dimerization resulting in constitutive PTK activation. The fusion protein exists as a 70-80 kDa doublet and was found to undergo homodimerization as well as heterodimerization with ETV6. Furthermore, we were able to show that the ETV6-NTRK3 protein acts as a PTK that was capable of interacting with PLCγ1, but not with other known NTRK3 interactors including SHC, SH2Bβ, GRB2 and PI3K. Moreover, ETV6-NTRK3 was shown to localize mainly in the cytoplasm. Our data support the notion that CFS is a biologically distinct entity, and ETV6-NTRK3 detection provides a diagnostic screening tool potentially useful in the clinical evaluation of children with spindle cell tumors.

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