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.
| Original language | English |
|---|---|
| Journal | International Journal of Cancer |
| DOIs | |
| Publication status | Published - Jan 1 2019 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations. / 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; Imoto, Seiya; Shibata, Tatsuhiro; Nakagawa, Hidewaki; Yamaguchi, Rui; Tanaka, Sakae; Matsuda, Koichi.
In: International Journal of Cancer, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations
AU - Tsuda, Yusuke
AU - Hirata, Makoto
AU - Katayama, Kotoe
AU - Motoi, Toru
AU - Matsubara, Daisuke
AU - Oda, Yoshinao
AU - Fujita, Masashi
AU - Kobayashi, Hiroshi
AU - Kawano, Hirotaka
AU - Nishida, Yoshihiro
AU - Sakai, Tomohisa
AU - Okuma, Tomotake
AU - Goto, Takahiro
AU - Ogura, Koichi
AU - Kawai, Akira
AU - Ae, Keisuke
AU - Anazawa, Ukei
AU - Suehara, Yoshiyuki
AU - Iwata, Shintaro
AU - Miyano, Satoru
AU - Imoto, Seiya
AU - Shibata, Tatsuhiro
AU - Nakagawa, Hidewaki
AU - Yamaguchi, Rui
AU - Tanaka, Sakae
AU - Matsuda, Koichi
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85066842367&partnerID=8YFLogxK
U2 - 10.1002/ijc.32421
DO - 10.1002/ijc.32421
M3 - Article
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
ER -