Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas.
Amino Acid Sequence
Base Sequence
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic
/ pathology
Humans
Inhibitory Concentration 50
Lymphatic Metastasis
/ pathology
Mutation
/ genetics
Oncogene Proteins, Fusion
/ genetics
Protein Multimerization
Proteins
/ chemistry
Proteogenomics
Proto-Oncogene Proteins c-ret
/ genetics
Thyroid Cancer, Papillary
/ genetics
Thyroid Neoplasms
/ genetics
Tumor Suppressor Proteins
/ metabolism
Ubiquitin
/ metabolism
Ubiquitin-Protein Ligases
/ metabolism
Ubiquitination
Up-Regulation
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 04 2020
28 04 2020
Historique:
received:
14
12
2018
accepted:
02
04
2020
entrez:
30
4
2020
pubmed:
30
4
2020
medline:
30
7
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32345963
doi: 10.1038/s41467-020-15955-w
pii: 10.1038/s41467-020-15955-w
pmc: PMC7188865
doi:
Substances chimiques
Oncogene Proteins, Fusion
0
Proteins
0
TFG protein, human
0
Tumor Suppressor Proteins
0
Ubiquitin
0
HUWE1 protein, human
EC 2.3.2.26
Ubiquitin-Protein Ligases
EC 2.3.2.27
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2056Subventions
Organisme : Medical Research Council
ID : MC_U105192713
Pays : United Kingdom
Références
National Cancer Institute. SEER Cancer Stat Facts: Thyroid Cancer https://seer.cancer.gov/statfacts/html/thyro.html (National Cancer Institute, Bethesda, MD).
National Cancer Institute. Cancer Stat Facts: Thyroid cancer. https://seer.cancer.gov/statfacts/html/thyro.html (National Cancer Institute, Bethesda, MD).
Lim, H. et al. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA 317, 1338–1348 (2017).
pubmed: 28362912
doi: 10.1001/jama.2017.2719
Kilfoy, B. A. et al. Gender is an age-specific effect modifier for papillary cancers of the thyroid gland. Cancer Epidemiol. Biomark. Prev. 18, 1092–1100 (2009).
doi: 10.1158/1055-9965.EPI-08-0976
Gilliland, F. D. et al. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973–1991. Cancer 79, 564–573 (1997).
pubmed: 9028369
doi: 10.1002/(SICI)1097-0142(19970201)79:3<564::AID-CNCR20>3.0.CO;2-0
Cardis, E. et al. Cancer consequences of the Chernobyl accident: 20 years on. J. Radio. Prot. 26, 127–140 (2006).
doi: 10.1088/0952-4746/26/2/001
Xing, M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer 13, 184–199 (2013).
pubmed: 23429735
pmcid: 3791171
doi: 10.1038/nrc3431
Luster, M. & Musholt, T. J. Thyroid gland: thyroid surgery and radioiodine ablation-the surgeon’s role. Nat. Rev. Endocrinol. 9, 140–141 (2013).
pubmed: 23183674
doi: 10.1038/nrendo.2012.229
Fedewa, S. A., Jemal, A. & Chen, A. Y. Trends and predictors of chemotherapy use among thyroid cancer patients in the national cancer database (2004–2013). Eur. Thyroid J. 5, 268–276 (2016).
pubmed: 28101492
pmcid: 5216190
doi: 10.1159/000449379
Sun, W. et al. Risk factors for central lymph node metastasis in CN0 papillary thyroid carcinoma: a systematic review and meta-analysis. PLoS ONE 10, e0139021 (2015).
pubmed: 26431346
pmcid: 4592212
doi: 10.1371/journal.pone.0139021
Carling, T. & Udelsman, R. Thyroid cancer. Annu Rev. Med. 65, 125–137 (2014).
pubmed: 24274180
doi: 10.1146/annurev-med-061512-105739
Williams, D. Cancer after nuclear fallout: lessons from the Chernobyl accident. Nat. Rev. Cancer 2, 543–549 (2002).
pubmed: 12094241
doi: 10.1038/nrc845
Nikiforova, M. N. et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290, 138–141 (2000).
pubmed: 11021799
doi: 10.1126/science.290.5489.138
Santoro, M., Melillo, R. M. & Fusco, A. RET/PTC activation in papillary thyroid carcinoma. Eur. J. Endocrinol. 155, 645–653 (2006).
pubmed: 17062879
doi: 10.1530/eje.1.02289
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014).
doi: 10.1016/j.cell.2014.09.050
Grieco, M. et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60, 557–563 (1990).
pubmed: 2406025
doi: 10.1016/0092-8674(90)90659-3
Moscat, J. et al. Cell signaling and function organized by PB1 domain interactions. Mol. Cell 23, 631–640 (2006).
pubmed: 16949360
doi: 10.1016/j.molcel.2006.08.002
Bienz, M. Signalosome assembly by domains undergoing dynamic head-to-tail polymerization. Trends Biochem Sci. 39, 487–495 (2014).
pubmed: 25239056
doi: 10.1016/j.tibs.2014.08.006
pmcid: 25239056
Kawamoto, Y. et al. Identification of RET autophosphorylation sites by mass spectrometry. J. Biol. Chem. 279, 14213–14224 (2004).
pubmed: 14711813
doi: 10.1074/jbc.M312600200
pmcid: 14711813
Myant, K. B. et al. HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. EMBO Mol. Med. 9, 181–197 (2017).
pubmed: 28003334
doi: 10.15252/emmm.201606684
Peter, S. et al. Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase. EMBO Mol. Med. 6, 1525–1541 (2014).
pubmed: 25253726
pmcid: 4287973
doi: 10.15252/emmm.201403927
Adhikary, S. et al. The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell 123, 409–421 (2005).
pubmed: 16269333
doi: 10.1016/j.cell.2005.08.016
Zhao, X. et al. The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev. Cell 17, 210–221 (2009).
pubmed: 19686682
pmcid: 2769073
doi: 10.1016/j.devcel.2009.07.009
Zhong, Q. et al. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095 (2005).
pubmed: 15989957
doi: 10.1016/j.cell.2005.06.009
Chen, D. et al. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121, 1071–1083 (2005).
pubmed: 15989956
doi: 10.1016/j.cell.2005.03.037
Mertens, F. et al. The emerging complexity of gene fusions in cancer. Nat. Rev. Cancer 15, 371–381 (2015).
pubmed: 25998716
doi: 10.1038/nrc3947
Staubitz, JuliaIsabelle et al. ANKRD26-RET - a novel gene fusion involving RET in papillary thyroid carcinoma. Cancer Genet. 238, 10–17 (2019).
pubmed: 31425920
doi: 10.1016/j.cancergen.2019.07.002
Staubitz, J. I. et al. Novel rearrangements involving the RET gene in papillary thyroid carcinoma. Cancer Genet. 230, 13–20 (2019).
pubmed: 30466862
doi: 10.1016/j.cancergen.2018.11.002
de Groot, J. W. et al. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr. Rev. 27, 535–560 (2006).
pubmed: 16849421
doi: 10.1210/er.2006-0017
Stransky, N. et al. The landscape of kinase fusions in cancer. Nat. Commun. 5, 4846 (2014).
pubmed: 25204415
pmcid: 4175590
doi: 10.1038/ncomms5846
Grubbs, E. G. et al. RET fusion as a novel driver of medullary thyroid carcinoma. J. Clin. Endocrinol. Metab. 100, 788–793 (2015).
pubmed: 25546157
doi: 10.1210/jc.2014-4153
Encinas, M. et al. Tyrosine 981, a novel ret autophosphorylation site, binds c-Src to mediate neuronal survival. J. Biol. Chem. 279, 18262–18269 (2004).
pubmed: 14766744
doi: 10.1074/jbc.M400505200
Rajalingam, K. & Dikic, I. SnapShot: expanding the ubiquitin code. Cell 164, 1074–1074 e1 (2016).
pubmed: 26919436
doi: 10.1016/j.cell.2016.02.019
Musholt, T. J. et al. Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques—a molecular and clinical analysis. Eur. J. Surg. Oncol. 45, 1018–1024 (2018).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
pubmed: 2705234
pmcid: 2705234
doi: 10.1093/bioinformatics/btp324
DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).
pubmed: 3083463
pmcid: 3083463
doi: 10.1038/ng.806
Saunders, C. T. et al. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28, 1811–1817 (2012).
pubmed: 22581179
doi: 10.1093/bioinformatics/bts271
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
pubmed: 27535533
pmcid: 5018207
doi: 10.1038/nature19057
Wu, T. D. & Nacu, S. Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26, 873–881 (2010).
pubmed: 20147302
pmcid: 2844994
doi: 10.1093/bioinformatics/btq057
Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).
pubmed: 20979621
pmcid: 20979621
doi: 10.1186/gb-2010-11-10-r106
Rudin, C. M. et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat. Genet. 44, 1111–1116 (2012).
pubmed: 22941189
pmcid: 3557461
doi: 10.1038/ng.2405
Wisniewski, J. R. et al. Universal sample preparation method for proteome analysis. Nat. Methods 6, 359–362 (2009).
doi: 10.1038/nmeth.1322
Distler, U. et al. Label-free quantification in ion mobility-enhanced data-independent acquisition proteomics. Nat. Protoc. 11, 795–812 (2016).
pubmed: 27010757
doi: 10.1038/nprot.2016.042
Hahne, H. et al. DMSO enhances electrospray response, boosting sensitivity of proteomic experiments. Nat. Methods 10, 989–991 (2013).
pubmed: 23975139
doi: 10.1038/nmeth.2610
Distler, U. et al. Drift time-specific collision energies enable deep-coverage data-independent acquisition proteomics. Nat. Methods 11, 167–170 (2014).
pubmed: 24336358
doi: 10.1038/nmeth.2767
Silva, J. C. et al. Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol. Cell Proteom. 5, 144–156 (2006).
doi: 10.1074/mcp.M500230-MCP200