Does <i><scp>CSF</scp>1</i> overexpression or rearrangement influence biological behaviour in tenosynovial giant cell tumours of the knee?

Mastboom, Monique J L; Hoek, D.M.; Bovée, Judith V.M.G.; Sande, Michiel A. J. van de; Szuhai, Károly

doi:10.1111/his.13744

Cited by 31 publications

(40 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found CSF1 alterations by FISH in 83% of all examined cases, including 80% of localized and 95% of diffuse‐type tenosynovial tumors in which FISH was successful, but only 60% of tumors of unspecified type, most of which were diagnosed on core biopsy or piecemeal excision. This was slightly higher than the 61%‐76% rearrangement rates reported in earlier series . Among positive cases, the population fraction of cells with CSF1 alterations (rearrangement and/or deletion) ranged from 2.1 to 30.7% (mean 11.9%), which is similar to the 2%‐25% in prior series .…”

Section: Discussionsupporting

confidence: 49%

“…For each tumor, at least 100 nuclei were scored for positive CSF1 translocated cases and 1000 nuclei were scored for negative cases to rule out rare events. The percent of nuclei bearing CSF1 3′ deletions (loss of one green signal), or CSF1 translocations (with separation of red and green‐labeled probes), were determined and positive deletion or translocation was defined as ≥2% of cells with deleted green signal or CSF1 split signals respectively, based on previous reports (Figure ) . Cases where both CSF1 3′ deletions and translocations were observed were considered as translocations for the purpose of analysis.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Peters

Dickson

et al. 2019

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 49%

Section: Methodsmentioning

confidence: 99%

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

Peters

Dickson

et al. 2019

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

show abstract

“…5 In 2013, the World Health Organization (WHO) classified TGCT into clinically distinct localized (TGCT-L) or diffuse types (TGCT-D), although both types are microscopically and genetically identical. 6,7 TGCT subtypes are associated with anatomic location: localized tumors (lobulated, well-circumscribed lesions) are more common in the digits of the hand, while diffuse tumors (aggressive lesions involving part or all of the synovial lining) are typically seen in large joints, most commonly the knee, followed by the hip. 2,7,8 Although TGCTs are chiefly benign, malignant TGCTs do exist.…”

Section: Epidemiologymentioning

confidence: 99%

“…6,7 TGCT subtypes are associated with anatomic location: localized tumors (lobulated, well-circumscribed lesions) are more common in the digits of the hand, while diffuse tumors (aggressive lesions involving part or all of the synovial lining) are typically seen in large joints, most commonly the knee, followed by the hip. 2,7,8 Although TGCTs are chiefly benign, malignant TGCTs do exist. A malignant TGCT is extremely rare, with fewer than 50 cases reported in the literature, and has a poor prognosis, with median survival of 22.5 months after diagnosis, despite aggressive treatment.…”

Section: Epidemiologymentioning

confidence: 99%

Pexidartinib and CSF1R Inhibitors as Treatment for Tenosynovial Giant Cell Tumors

Granger¹,

Subhawong²,

D’Amato³

et al. 2021

Oncology &Amp; Hematology Review (US)

View full text Add to dashboard Cite

“…Two subtypes of TGCT are de ned based on clinical and radiological characteristics: localized-and diffusetype TGCT (L-TGCT and dt-TGCT) [2,3]. Although both subtypes share a common pathophysiology, they represent a wide spectrum of clinical entities, making TGCT behavior complex and hard to predict [4]. From the molecular point of view, both subtypes usually share the presence of a fusion involving the colony stimulating factor (CSF) gene, which drives tumor growth [5,6].…”

Section: Introductionmentioning

confidence: 99%

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective real-world study

Bernthal¹,

Spierenburg²,

Healey³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Tenosynovial giant cell tumor (TGCT) is a rare locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. The majority of findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study explores prospectively the real-world management of TGCT.Methods: The TGCT Observational Platform Project (TOPP) registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, and 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%), and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases.

show abstract

Does CSF1 overexpression or rearrangement influence biological behaviour in tenosynovial giant cell tumours of the knee?

Cited by 31 publications

References 33 publications

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

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

Pexidartinib and CSF1R Inhibitors as Treatment for Tenosynovial Giant Cell Tumors

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective real-world study

Contact Info

Product

Resources

About