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Molecular characterization of pediatric spindle cell tumors Knezevich, Stevan Robert
Abstract
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.
Item Metadata
Title |
Molecular characterization of pediatric spindle cell tumors
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2000
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Description |
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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Extent |
9508192 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-07-15
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0089630
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2000-05
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.