PXD016739

PXD016739 is an original dataset announced via ProteomeXchange.

Title	Proteogenomics analysis unveils a novel TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas
Description	Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. From a set of PTC patients whose tumor did not harbour any BRAF or RAS mutations, a 35 years old male patient’s normal, primary tumor and lymph node (LN) metastatic tissues was subjected to genomics and proteomics analysis. By RNA-seq analysis, we identified a novel RET rearrangement involving 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. Further, TFG-RET oncogene oligomerises in a PB1 domain dependent manner and consistently, mutation of the oligomerisation interface led to the inhibition of RET-mediated oncogenic transformation. Quantitative proteomic analysis of the same samples revealed the upregulation of proteins involved in the ubiquitination machinery including HECT carrying E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in the tumor and LN metastatic lesions. We further identify that expression of TFG-RET led to the upregulation of HUWE1. Further, in a cohort of PTC patients, we observed higher expression of HUWE1, USP9X and USP7 in the tumor and metastatic lesions, when compared to the matched normal tissue. Transient knockdown of HUWE1, USP9X and USP7 affected viability and proliferation of TFG-RET transformed cells. Consistently, inhibition of RET, HUWE1 and DUBs by small molecule inhibitors significantly reduced RET-mediated oncogenesis. Apart from unveiling a novel oncogenic RET fusion in PTCs, our data may open a novel avenue of targeting ubiquitin signaling machinery in human PTCs.
HostingRepository	PRIDE
AnnounceDate	2020-04-02
AnnouncementXML	Submission_2020-06-12_04:30:22.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Malte Sielaff
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2019-12-13 07:42:08	ID requested
1	2020-04-01 22:48:17	announced
⏵ 2	2020-06-12 04:30:23	announced	2020-06-12: Updated publication reference for PubMed record(s): 32345963.

Krishnan A, Berthelet J, Renaud E, Rosigkeit S, Distler U, Stawiski E, Wang J, Modrusan Z, Fiedler M, Bienz M, Tenzer S, Schad A, Roth W, Thiede B, Seshagiri S, Musholt TJ, Rajalingam K, Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas. Nat Commun, 11(1):2056(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: PTC, RET, HUWE1, USP7, USP9X, Precision medicine, TFG-RET

Stefan Tenzer
contact affiliation	Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
contact email	tenzer@uni-mainz.de
lab head
Malte Sielaff
contact affiliation	University Medical Center Mainz
contact email	malte.sielaff@uni-mainz.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/04/PXD016739

PRIDE project URI

• PRIDE
  1. PXD016739
     1. Label: PRIDE project
     2. Name: Proteogenomics analysis unveils a novel TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas