Detection of CSF1 rearrangements deleting the 3′ UTR in tenosynovial giant cell tumors

Abstract

Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements of 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 five 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 six of 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.

SETDB1 Promotes the Growth of Glioma via CSF-1-dependent Macrophage Recruitment by Activating the AKT/mTOR Signaling Pathway

“…One feature that is encouraging here is identi cation of safeapplicationsof immunotherapeutic or standard treatment tools [41][42][43]. Such promising activity has been demonstrated in autocrine CSF-1-based benign diffuse-type tenosynovial giant cell tumors [44,45].…”

SETDB1 promotes glioblastoma growth via CSF-1 - dependent macrophage recruitment by activating the AKT/mTOR signaling pathway

“…One feature that is encouraging here is identi cation of safe applications of immunotherapeutic or standard treatment tools [48][49][50]. Such promising activity has been demonstrated in autocrine CSF-1-based benign diffuse-type tenosynovial giant cell tumors [51,52]. In the case of malignant disorders, reports from clinical perspectives have yet to be explored.…”

<p>The Biological Role of the Collagen Alpha-3 (VI) Chain and Its Cleaved C5 Domain Fragment Endotrophin in Cancer</p>

“…TGCTs are derived from the overexpression of rearranged macrophage colony-stimulating factor (CSF1), which causes tumor growth and recruitment of nonneoplastic mononuclear and multinucleated inflammatory cells. [85][86][87] Previous studies have confirmed the existence of the fusion gene CSF1-COL6A3 in TGCTs by RT-PCR. Due to a strong COL6A3 promoter, a fusion of the CSF1-COL6A3 genes through the translocation would result in overexpression of CSF1.…”

“…85,86 However, recently, in a large cohort study, TGCTs were reported to feature truncation of the 3ʹ end of CSF1 and were characterized by variable alterations, not the previously identified COL6A3-CSF1 fusion genes found in some TGCTs. 87…”