Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations

Yusuke Tsuda, Makoto Hirata, Kotoe Katayama, Toru Motoi, Daisuke Matsubara, Yoshinao Oda, Masashi Fujita, Hiroshi Kobayashi, Hirotaka Kawano, Yoshihiro Nishida, Tomohisa Sakai, Tomotake Okuma, Takahiro Goto, Koichi Ogura, Akira Kawai, Keisuke Ae, Ukei Anazawa, Yoshiyuki Suehara, Shintaro Iwata, Satoru MiyanoSeiya Imoto, Tatsuhiro Shibata, Hidewaki Nakagawa, Rui Yamaguchi, Sakae Tanaka, Koichi Matsuda

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3276-3284
Number of pages9
JournalInternational Journal of Cancer
Issue number12
Publication statusPublished - Dec 15 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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