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

Aswini Krishnan, Jean Berthelet, Emilie Renaud, Sebastian Rosigkeit, Ute Distler, Eric Stawiski, Jing Wang, Zora Modrusan, Marc Fiedler, Mariann Bienz, Stefan Tenzer, Arno Schad, Wilfried Roth, Bernd Thiede, Somasekar Seshagiri, Thomas J. Musholt and Krishnaraj Rajalingam ()
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Aswini Krishnan: University Medical Center of the Johannes Gutenberg University Mainz
Jean Berthelet: University Medical Center of the Johannes Gutenberg University Mainz
Emilie Renaud: University Medical Center of the Johannes Gutenberg University Mainz
Sebastian Rosigkeit: University Medical Center of the Johannes Gutenberg University Mainz
Ute Distler: University Medical Center of the Johannes Gutenberg University Mainz
Eric Stawiski: MedGenome, Inc.
Jing Wang: MedGenome, Inc.
Zora Modrusan: Genentech, Inc.
Marc Fiedler: MRC Laboratory of Molecular Biology
Mariann Bienz: MRC Laboratory of Molecular Biology
Stefan Tenzer: University Medical Center of the Johannes Gutenberg University Mainz
Arno Schad: University Medical Center Mainz
Wilfried Roth: University Medical Center Mainz
Bernd Thiede: University of Oslo
Somasekar Seshagiri: Genentech, Inc.
Thomas J. Musholt: University Medicine
Krishnaraj Rajalingam: University Medical Center of the Johannes Gutenberg University Mainz

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15955-w

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