Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations.
Exons
/ genetics
Female
Giant Cell Tumor of Tendon Sheath
/ genetics
High-Throughput Nucleotide Sequencing
/ methods
Humans
Macrophage Colony-Stimulating Factor
/ genetics
Male
Mutation
/ genetics
Neoplasm Recurrence, Local
/ genetics
Recombinant Fusion Proteins
/ genetics
Sequence Analysis, RNA
/ methods
Translocation, Genetic
/ genetics
CBL mutation
CSF1 fusion transcript
RNA sequence
tenosynovial giant cell tumors
whole-exome sequence
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 12 2019
15 12 2019
Historique:
received:
18
01
2019
revised:
10
04
2019
accepted:
30
04
2019
pubmed:
21
5
2019
medline:
31
1
2020
entrez:
21
5
2019
Statut:
ppublish
Résumé
Tenosynovial giant cell tumor (TSGCT) is a rare neoplasm. Although surgical resection is the widely accepted primary treatment for TSGCT, recurrences are frequent, and patients' joint function may be severely compromised. Previous studies reported that CSF1-COL6A3 fusion genes were identified in approximately 30% of TSGCTs. The aim of our study was to comprehensively clarify the genomic abnormalities in TSGCTs. We performed whole exome sequencing in combination with target sequence validation on 34 TSGCT samples. RNA sequencing was also performed on 18 samples. RNA sequencing revealed fusion transcripts involving CSF1, including novel CSF1-VCAM1, CSF1-FN1 and CSF1-CDH1 fusions, in 13/18 (72%) cases. These fusion genes were validated by chromogenic in situ hybridization. All CSF1 fusions resulted in the deletion of CSF1 exon 9, which was previously shown to be an important negative regulator of CSF1 expression. We also found that 12 (35%) of the 34 TSGCT samples harbored CBL missense mutations. All mutations were detected in exons 8 or 9, which encode the linker and RING finger domain. Among these mutations, C404Y, L380P and R420Q were recurrent. CBL-mutated cases showed higher JAK2 expression than wild-type CBL cases (p = 0.013). CSF1 fusion genes and CBL mutations were not mutually exclusive, and both alterations were detected in six of the 18 (33%) tumors. The frequent deletion of CSF1 exon 9 in the fusion transcripts suggested the importance of this event in the etiology of TSGCT. Our results may contribute to the development of new targeted therapies using JAK2 inhibitors for CBL-mutated TSGCT.
Substances chimiques
CSF1 protein, human
0
Recombinant Fusion Proteins
0
Macrophage Colony-Stimulating Factor
81627-83-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3276-3284Informations de copyright
© 2019 UICC.
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