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.
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.
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