Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations
Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations
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DOI：
10.1002/ijc.32421
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发表时间：
2019-12-15
影响因子：
6.4
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
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作者：
Tsuda, Yusuke;Hirata, Makoto;Matsuda, Koichi
腱鞘巨细胞瘤是一种罕见的肿瘤。虽然手术切除是广泛接受的TSGCT的主要治疗方法，但复发频繁，患者的关节功能可能严重受损。先前的研究报道，在大约30%的TSGCT中鉴定出CSF 1-COL 6A 3融合基因。本研究的目的是全面阐明TSGCTs的基因组异常。我们对34个TSGCT样本进行了全外显子组测序和靶序列验证。还对18个样品进行了RNA测序。RNA测序显示，在13/18例（72%）病例中，融合转录物涉及CSF 1，包括新型CSF 1-VCAM 1、CSF 1-FN 1和CSF 1-CDH 1融合。这些融合基因通过显色原位杂交进行了验证。所有CSF 1融合导致CSF 1外显子9的缺失，其先前被证明是CSF 1表达的重要负调节因子。我们还发现34例TSGCT样本中有12例（35%）携带CBL错义突变。所有突变均在编码接头和RING指结构域的外显子8或9中检测到。在这些突变中，C404 Y、L380 P和R420 Q是复发性的。CBL突变病例显示JAK 2表达高于野生型CBL病例（p = 0.013）。CSF 1融合基因和CBL突变并不相互排斥，在18例肿瘤中的6例（33%）中检测到这两种改变。融合转录本中CSF 1外显子9的频繁缺失表明该事件在TSGCT病因学中的重要性。我们的研究结果可能有助于使用JAK 2抑制剂开发CBL突变的TSGCT的新靶向治疗。
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.