Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas
Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas
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DOI：
10.1038/s41467-020-15955-w
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发表时间：
2020-04-28
影响因子：
16.6
通讯作者：
Rajalingam, Krishnaraj
中科院分区：
文献类型：
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作者：
Krishnan, Aswini;Berthelet, Jean;Rajalingam, Krishnaraj
甲状腺乳头状癌（PTC）是最常见的内分泌恶性肿瘤。通过RNA-seq分析，我们在一名没有任何已知RAS或BRAF突变的患者的肿瘤材料中鉴定出RET重排。这种新的基因融合涉及来自Trk融合基因（TFG）的5 '端的外显子1-4与RET酪氨酸激酶的3 '端融合，导致TFG-RET融合，其以激酶依赖性方式转化永生化的人甲状腺细胞。TFG-RET以PB 1结构域依赖性方式寡聚化，并且TFG-RET的寡聚化是致癌转化所需的。定量蛋白质组学分析揭示了E3泛素连接酶HUWE 1和DUB（如USP 9 X和UBP 7）在肿瘤和转移性病变中的上调，这在其他患者中得到了进一步证实。TFG-RET的表达导致HUWE 1的上调，并且HUWE 1的抑制显著降低RET介导的肿瘤发生。pid =Par甲状腺乳头状癌（PTC）是最常见的内分泌恶性肿瘤之一。在这里，作者使用蛋白质基因组学方法分析原发性肿瘤和淋巴结转移的PTC患者，并报告了致癌RET融合，和潜在的药物靶点从泛素信号机制治疗人PTC。
Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5 end of the Trk fused Gene (TFG) fused to the 3 ' end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis. p id=Par Papillary thyroid cancer (PTC) is one of the most common type of endocrine malignancy. Here, the authors use proteogenomic approaches to analyse the primary tumour and lymph node metastases from a PTC patient and report an oncogenic RET fusion, and potential druggable targets from the ubiquitin signaling machinery for treating human PTCs.