Abstract
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.
Highlights
Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy
We have extended the proteomic analysis further to 4 more patients and we consistently identified HUWE1 as one of the prime factors that are upregulated in the tumor and metastatic lesions (Fig. 5b, c, Supplementary Fig. 5C and Supplementary Data 6)
A TCGA study that aimed at the genomic characterization of 496 PTCs illustrated the mutual exclusivity of genetic driver alterations in PTCs, which further emphasizes the importance of precision medicine in the treatment of cancer[15]
Summary
By RNAseq 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 kinasedependent manner. By employing proteogenomic analysis of matching normal vs tumor vs lymph node metastasis of the same patient, we identified and validated a novel oncogenic RET fusion as well as other druggable targets in PTCs. We extended our proteomics observations by analyzing a cohort of PTC patient samples. We provide mechanistic insights on the activation of the TFG-RET fusion and identified that E3 ubiquitin ligase HUWE1 is required for RET-mediated oncogenic transformation
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