Pigmented villonodular synovitis/diffuse-type tenosynovial giant cell tumor: Opening options in management
DRUGS OF THE FUTURE
Authors: Eberst, L.; Brahmi, M.; Blay, J. -Y.; Cassier, P. A.
Abstract
Pigmented villonodular synovitis (PVNS), alternatively known as diffuse-type tenosynovial giant cell tumor (D-TGCT), is a rare joint disease tumor affecting young adults. Standard management requires iterative surgery, which may significantly impact quality of life. The molecular hallmark is a chromosomal translocation resulting in the fusion of an isotype of collagen with colony-stimulating factor 1 (CSF1) by the tumor cell component. This leads to an overproduction of the cytokine and the recruitment of CSF1-receptor (CSF1R)-expressing macrophages, eventually forming a locally destructive proliferation. TGCT is therefore considered as a neoplastic proliferation, locally aggressive and very rarely metastatic. CSF1R inhibitors have the potential to inhibit this pathogenetic loop, and are currently under investigation in several clinical trials. These inhibitors include small molecules like imatinib, nilotinib and pexidartinib, and monoclonal antibodies such as emactuzumab, MCS-110 and FPA-008. Preliminary efficacy data suggests that these drugs have the potential to modify the current management of D-TGCT. As CSF1 is also implicated in protumoral macrophage polarization, CSF1R inhibitors are also tested in combination with other immunotherapies in a wide variety of solid tumors. This review aims to describe the future management of D-TGCT in the era of CSF1R inhibitors.
Detection of CSF1 rearrangements deleting the 3 ' UTR in tenosynovial giant cell tumors
GENES CHROMOSOMES & CANCER
Authors: Ho, Julie; Peters, Thomas; Dickson, Brendan C.; Swanson, David; Fernandez, Anita; Frova-Seguin, Aurelie; Valentin, Marie-Anne; Schramm, Ursula; Sultan, Marc; Nielsen, Torsten O.; Demicco, Elizabeth G.
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.
COA
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