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- Title
Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations.
- Authors
Tsuda, Yusuke; Hirata, Makoto; Katayama, Kotoe; Motoi, Toru; Matsubara, Daisuke; Oda, Yoshinao; Fujita, Masashi; Kobayashi, Hiroshi; Kawano, Hirotaka; Nishida, Yoshihiro; Sakai, Tomohisa; Okuma, Tomotake; Goto, Takahiro; Ogura, Koichi; Kawai, Akira; Ae, Keisuke; Anazawa, Ukei; Suehara, Yoshiyuki; Iwata, Shintaro; Miyano, Satoru
- Abstract
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. What's new? The CSF1‐COL6A3 fusion gene has been detected in a third of tenosynovial giant cell tumor (TSGCT) cases, but additional signaling pathways or mutations may be involved. Here, RNA sequencing reveals several fusion transcripts involving CSF1, including novel CSF1‐VCAM1, CSF1‐FN1 and CSF1‐CDH1 fusions, in 72% of TSGCT cases. All CSF1 fusion transcripts result in the deletion of CSF1 exon 9, a negative regulator of CSF1 expression. Moreover, novel CBL mutations are found in 35% of tumors, with or without the presence of CSF1 fusions. The data may contribute to the development of new targeted therapies and reveal the etiology of TSGCT.
- Subjects
SOMATIC mutation; GENE fusion; RNA sequencing; GIANT cell tumors; IN situ hybridization; MISSENSE mutation
- Publication
International Journal of Cancer, 2019, Vol 145, Issue 12, p3276
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.32421