A TFG-RET fusion was found in a papillary thyroid carcinoma.

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 do 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. Proteomic analysis of the same samples 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 that inhibition of RET, HUWE1 and DUBs by small molecule inhibitors significantly reduces RET-mediated oncogenesis.