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Calebiro, D.* ; Grassi, E.S.* ; Eszlinger, M.* ; Ronchi, C.L.* ; Godbole, A.* ; Bathon, K.* ; Guizzardi, F.* ; de Filippis, T.* ; Krohn, K.* ; Jaeschke, H.* ; Schwarzmayr, T. ; Bircan, R.* ; Gozu, H.I.* ; Sancak, S.* ; Niedziela, M.* ; Strom, T.M. ; Fassnacht, M.* ; Persani, L.* ; Paschke, R.*

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas.

J. Clin. Invest. 126, 3383-3388 (2016)
Verlagsversion DOI PMC
Open Access Gold
Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein α 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Somatic Mutations; Constitutive Activation; Germline Mutation; Hyperthyroidism
Sprache
Veröffentlichungsjahr 2016
HGF-Berichtsjahr 2016
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 126, Heft: 9, Seiten: 3383-3388 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort Ann Arbor
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
DOI 10.1172/JCI84894
WOS ID WOS:000382513400020
Scopus ID 84987792301
PubMed ID 27500488
Erfassungsdatum 2016-09-06
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