Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

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dc.authorid0000-0001-8862-6937
dc.authorid0000-0001-5291-8620
dc.authorid0000-0003-2068-9581
dc.authorid0000-0001-6170-6398
dc.authorid0000-0002-4732-2934
dc.authorid0000-0001-5020-2071
dc.authorid0000-0002-3811-1553
dc.authorscopusid8851877800
dc.authorscopusid43761202200
dc.authorscopusid57195256086
dc.authorscopusid7005205446
dc.authorscopusid56494642600
dc.authorscopusid56525211000
dc.authorscopusid8618109600
dc.authorwosidNiedziela, Marek/A-1155-2011
dc.authorwosidBircan, Rıfat/A-7344-2018
dc.authorwosidPersani, Luca/B-6543-2008
dc.authorwosidde Filippis, Tiziana/AAA-8511-2020
dc.authorwosidFassnacht, Martin/N-9614-2019
dc.authorwosidGrassi, Elisa Stellaria/K-4402-2016
dc.contributor.authorCalebiro, Davide
dc.contributor.authorGrassi, Elisa S.
dc.contributor.authorEszlinger, Markus
dc.contributor.authorRonchi, Cristina L.
dc.contributor.authorGodbole, Amod
dc.contributor.authorBathon, Kerstin
dc.contributor.authorPaschke, Ralf
dc.contributor.authorBircan, Rifat
dc.date.accessioned2022-05-11T14:28:35Z
dc.date.available2022-05-11T14:28:35Z
dc.date.issued2016
dc.departmentFakülteler, Fen Edebiyat Fakültesi, Biyoloji Bölümü
dc.description.abstractAutonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein alpha subunit (GNAS) are found in approximately 70% of ATAs. The involvement of other genes and the pathogenesis of the remaining cases are presently unknown. Here, we performed whole-exome sequencing in 19 ATAs that were paired with normal DNA samples and identified a recurrent hot-spot mutation (c.1712A>G; p.Gln571Arg) in the enhancer of zeste homolog 1 (EZH1) gene, which codes for a catalytic subunit of the polycomb complex. Targeted screening in an independent cohort confirmed that this mutation occurs with high frequency (27%) in ATAs. EZH1 mutations were strongly associated with known (TSHR, GNAS) or presumed (adenylate cyclase 9 [ADCY9]) alterations in cAMP pathway genes. Furthermore, functional studies revealed that the p.Gln571Arg EZH1 mutation caused increased histone H3 trimethylation and increased proliferation of thyroid cells. In summary, this study revealed that a hot-spot mutation in EZH1 is the second most frequent genetic alteration in ATAs. The association between EZH1 and TSHR mutations suggests a 2-hit model for the pathogenesis of these tumors, whereby constitutive activation of the cAMP pathway and EZH1 mutations cooperate to induce the hyperproliferation of thyroid cells.
dc.description.sponsorshipIZKF Wurzburg [B-281]; ERA-NET E-Rare [01GM1407B]; Deutsche KrebshilfeDeutsche Krebshilfe [109994]; Wilhelm Sander Stiftung [2013.010.1]
dc.description.sponsorshipWe wish to thank Eileen Bosenberg, Bianca Klupfel, and Ines Elsner for technical support and Ulrike Zabel for DNA cloning. This study was partially supported by grants from the IZKF Wurzburg (B-281, to DC and MF); the ERA-NET E-Rare (01GM1407B, to MF and DC); the Deutsche Krebshilfe (109994, to ME); and the Wilhelm Sander Stiftung (project 2013.010.1, to RP).
dc.identifier.doi10.1172/JCI84894
dc.identifier.endpage3388
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.issue9en_US
dc.identifier.pmid27500488
dc.identifier.scopus2-s2.0-84987792301
dc.identifier.scopusqualityQ1
dc.identifier.startpage3383
dc.identifier.urihttps://doi.org/10.1172/JCI84894
dc.identifier.urihttps://hdl.handle.net/20.500.11776/6877
dc.identifier.volume126
dc.identifier.wosWOS:000382513400020
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorBircan, Rifat
dc.language.isoen
dc.publisherAmer Soc Clinical Investigation Inc
dc.relation.ispartofJournal of Clinical Investigation
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectSomatic Mutations
dc.subjectConstitutive Activation
dc.subjectGermline Mutation
dc.subjectHyperthyroidism
dc.titleRecurrent EZH1 mutations are a second hit in autonomous thyroid adenomas
dc.typeArticle

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