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

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.

SUBMITTER: Krishnan A

PROVIDER: S-EPMC7188865 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Krishnan Aswini A Berthelet Jean J Renaud Emilie E Rosigkeit Sebastian S Distler Ute U Stawiski Eric E Wang Jing J Modrusan Zora Z Fiedler Marc M Bienz Mariann M Tenzer Stefan S Schad Arno A Roth Wilfried W Thiede Bernd B Seshagiri Somasekar S Musholt Thomas J TJ Rajalingam Krishnaraj K

Nature communications 20200428 1

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-depen ...[more]

PMID: 32345963

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Project description:Synopsis for table of contentsAn exceptional number of synchronous MTC/PTC in the same thyroid gland is presented. This may be the most numerous case series reported in the literature. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes and the clinical and pathological aspects as well as the results are presented.Background and objectivesThe synchronous occurrence of multiple neoplastic processes in the thyroid gland is unusual. We investigated the clinicopathological features of 30 medullary thyroid carcinomas (MTC) in association with papillary (PTC).MethodRetrospective analysis of operated patients for thyroid tumors. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes: (type I) True mixed MTC/PTC, MTC and PTC closely intermingled. (Type II) Collision MTC/PTC, i.e. tumors that meet at the same site, invade each other and appear as a single mass in the thyroid gland, i.e. MTC and PTC merge. (Type III) Synchronous anatomically separate tumors in the same thyroid lobe, i.e. separated from each other by non-tumorous thyroid parenchyma. (Type IV) Synchronous tumors occurring in separate anatomical lobes or in the isthmus. Clinical and pathological data were reviewed. Location: Department of thyroid surgery, China-Japan Union Hospital, Jilin University. Time frame: 14 years (June 2008-November 2022).ResultsThirty patients were identified with an overall prevalence of 28621 (0.1%). 17 (56.7%) were male, 13 (43.3%) female, mean age 51.3 ± 11.0 years, mean BMI 23.6 ± 3.6kg/m2. Mean duration of symptoms was 11.2 ± 18.4 months. Mean calcitonin level was 133.7 ± 196.4 pg/ml. Fine needle aspiration (FNA) was offered in 21 cases: 9 (42.9%) were suspected carcinoma, 9 (42.9%) PTC, 1 (4.8%) MTC, 2 (9.4%) MTC/PTC. Pathology revealed type I 4 (13.3%), type II 2 (6.7%), type III 14 (46.7%), type IV 10 (33.3%). The mean diameter of MTC was 1.6 ± 2.0cm, 18 (60%) were micro-MTC. The mean diameter of PTC was 0.9 ± 1.9 cm, 26 (86.7%) were micro-PTC. In 16 (53.3%) micro-PTC/-MTC occurred in synchronous sequence. Four patients had a recurrence: 2 had to be re-operated due to MTC recurrence, 2 died due to distant metastases (bone, liver).ConclusionWe report an exceptional number of MTC/PTC in the same thyroid gland. This may be the most numerous case series reported in the literature. The clinical and pathological aspects as well as the results are presented.

Dataset Information

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

Publications

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

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