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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Papillary thyroid cancer (PTC) is the most common endocrine malignancy.
• Identifying novel driver mutations is crucial for understanding PTC pathogenesis.
• Known mutations like RAS and BRAF are common in PTC, but some cases lack these drivers.

Purpose of the Study:

• To identify novel genetic alterations in PTC patients lacking common mutations.
• To characterize the oncogenic potential of newly identified gene fusions.
• To investigate the molecular mechanisms underlying TFG-RET-driven thyroid cancer.

Main Methods:

• RNA sequencing (RNA-seq) analysis of tumor samples.
• Creation and functional analysis of TFG-RET fusion constructs in immortalized human thyroid cells.
• Oligomerization studies using the PB1 domain.
• Quantitative proteomic analysis.
• Inhibition studies targeting HUWE1.

Main Results:

• A novel TFG-RET fusion gene was identified in a PTC patient negative for RAS/BRAF mutations.
• The TFG-RET fusion transforms thyroid cells in a kinase-dependent manner.
• TFG-RET oligomerization via its PB1 domain is essential for oncogenic transformation.
• Upregulation of E3 ubiquitin ligase HUWE1 and deubiquitinases (DUBs) like USP9X and UBP7 was observed in tumor and metastatic samples.
• TFG-RET expression induces HUWE1 upregulation, and its inhibition reduces oncogenesis.

Conclusions:

• The TFG-RET fusion represents a novel oncogenic driver in a subset of papillary thyroid cancer.
• TFG-RET-mediated oncogenesis involves kinase activity, oligomerization, and upregulation of HUWE1.
• Targeting HUWE1 may offer a therapeutic strategy for TFG-RET-driven thyroid cancers.