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Detection of CSF1 Rearrangements Deleting the 3'UTR in Tenosynovial Giant Cell Tumors Ho, Julie; Peters, Thomas; Dickson, Brendan C.; Swanson, David; Fernandez, Anita; Frova-Seguin, Aurelie; Valentin, Marie-Anne; Schramm, Ursula; Sultan, Marc; Nielsen, Torsten; Demicco, Elizabeth G.

Abstract

Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements in CSF1, thought to drive overexpression of macrophage colony-stimulating factor (CSF1), thereby promoting tumor growth and recruitment of non-neoplastic mononuclear and multinucleated inflammatory cells. While fusions to collagen promoters have been described, the mechanism of CSF1 overexpression has been unclear in a majority of cases. Two cohorts of TGCT were investigated for CSF1 rearrangements using fluorescence in situ hybridization (FISH) and either RNA-seq or DNA-seq with Sanger validation. The study comprised 39 patients, including 13 localized TGCT, 21 diffuse TGCT, and 5 of unspecified type. CSF1 rearrangements were identified by FISH in 30 cases: 13 translocations, 17 3’ deletions. Sequencing confirmed CSF1 breakpoints in 28 cases; in all 28 the breakpoint was found to be downstream of exon 5, replacing or deleting a long 3’UTR containing known miRNA and AU-rich element negative regulatory sequences. We also confirmed the presence of CBL exon 8-9 mutations in 6/21 cases. In conclusion, TGCT in our large cohort were characterized by variable alterations, all of which led to truncation of the 3’ end of CSF1, instead of the COL6A3-CSF1 fusions previously reported in some TGCTs. The diversity of fusion partners but consistent integrity of CSF1 functional domains encoded by exons 1-5 support a hypothesis that CSF1 overexpression results from transcription of a truncated form of CSF1 lacking 3' negative regulatory sequences. The presence of CBL mutations affecting the linker and RING finger domain suggests an alternative mechanism for increased CSF1/CSF1R signaling in some cases.

Item Metadata

Title
Detection of CSF1 Rearrangements Deleting the 3'UTR in Tenosynovial Giant Cell Tumors
Alternate Title
CSF1 in tenosynovial giant cell tumor
Creator
Ho, Julie; Peters, Thomas; Dickson, Brendan C.; Swanson, David; Fernandez, Anita; Frova-Seguin, Aurelie; Valentin, Marie-Anne; Schramm, Ursula; Sultan, Marc; Nielsen, Torsten; Demicco, Elizabeth G.
Contributor
Genetic Pathology Evaluation Centre.
Publisher
Wiley-Blackwell
Date Issued
2020-02
Description
Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements in CSF1, thought to drive overexpression of macrophage colony-stimulating factor (CSF1), thereby promoting tumor growth and recruitment of non-neoplastic mononuclear and multinucleated inflammatory cells. While fusions to collagen promoters have been described, the mechanism of CSF1 overexpression has been unclear in a majority of cases. Two cohorts of TGCT were investigated for CSF1 rearrangements using fluorescence in situ hybridization (FISH) and either RNA-seq or DNA-seq with Sanger validation. The study comprised 39 patients, including 13 localized TGCT, 21 diffuse TGCT, and 5 of unspecified type. CSF1 rearrangements were identified by FISH in 30 cases: 13 translocations, 17 3’ deletions. Sequencing confirmed CSF1 breakpoints in 28 cases; in all 28 the breakpoint was found to be downstream of exon 5, replacing or deleting a long 3’UTR containing known miRNA and AU-rich element negative regulatory sequences. We also confirmed the presence of CBL exon 8-9 mutations in 6/21 cases. In conclusion, TGCT in our large cohort were characterized by variable alterations, all of which led to truncation of the 3’ end of CSF1, instead of the COL6A3-CSF1 fusions previously reported in some TGCTs. The diversity of fusion partners but consistent integrity of CSF1 functional domains encoded by exons 1-5 support a hypothesis that CSF1 overexpression results from transcription of a truncated form of CSF1 lacking 3' negative regulatory sequences. The presence of CBL mutations affecting the linker and RING finger domain suggests an alternative mechanism for increased CSF1/CSF1R signaling in some cases.
Subject
Tenosynovial giant cell tumor; pigmented villonodular synovitis; CSF1; CBL; 3’UTR
Genre
Article; Postprint
Type
Text
Language
eng
Date Available
2021-05-17
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0397500
URI
http://hdl.handle.net/2429/78358
Affiliation
Medicine, Faculty of; Non UBC; Pathology and Laboratory Medicine, Department of
Citation
Ho J, Peters T, Dickson BC, Swanson D, Fernandez A, Frova-Seguin A, Valentin MA, Schramm U, Sultan M, Nielsen TO, Demicco EG. Detection of CSF1 rearrangements deleting the 3' UTR in tenosynovial giant cell tumors. Genes Chromosomes Cancer. 2020 Feb;59(2):96-105
Publisher DOI
10.1002/gcc.22807
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
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Attribution-NonCommercial-NoDerivatives 4.0 International