Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas.
Aswini KrishnanJean BertheletEmilie RenaudSebastian RosigkeitUte DistlerEric StawiskiJing WangZora ModrusanMarc FiedlerMariann BienzStefan TenzerArno SchadWilfried RothBernd ThiedeSomasekar SeshagiriThomas J MusholtKrishnaraj RajalingamPublished in: Nature communications (2020)
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.
Keyphrases
- tyrosine kinase
- rna seq
- poor prognosis
- end stage renal disease
- genome wide
- copy number
- single cell
- squamous cell carcinoma
- papillary thyroid
- endothelial cells
- cell proliferation
- ejection fraction
- epidermal growth factor receptor
- chronic kidney disease
- induced apoptosis
- signaling pathway
- newly diagnosed
- lymph node metastasis
- case report
- oxidative stress
- gene expression
- high resolution
- risk assessment
- binding protein
- patient reported outcomes
- mass spectrometry
- induced pluripotent stem cells
- pluripotent stem cells