Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas

Nat Commun. 2020 Apr 28;11(1):2056. doi: 10.1038/s41467-020-15955-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic / pathology
  • Humans
  • Inhibitory Concentration 50
  • Lymphatic Metastasis / pathology
  • Mutation / genetics
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Protein Multimerization
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism
  • Proteogenomics*
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Thyroid Cancer, Papillary / genetics*
  • Thyroid Neoplasms / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Up-Regulation


  • Oncogene Proteins, Fusion
  • Proteins
  • TFG protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin
  • HUWE1 protein, human
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-ret