title: Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas.
abstract: 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.
authors: Davide
authors: D
authors: Calebiro
authors: Elisa S
authors: ES
authors: Grassi
authors: Markus
authors: M
authors: Eszlinger
authors: Cristina L
authors: CL
authors: Ronchi
authors: Amod
authors: A
authors: Godbole
authors: Kerstin
authors: K
authors: Bathon
authors: Fabiana
authors: F
authors: Guizzardi
authors: Tiziana
authors: T
authors: de Filippis
authors: Knut
authors: K
authors: Krohn
authors: Holger
authors: H
authors: Jaeschke
authors: Thomas
authors: T
authors: Schwarzmayr
authors: Rifat
authors: R
authors: Bircan
authors: Hulya Iliksu
authors: HI
authors: Gozu
authors: Seda
authors: S
authors: Sancak
authors: Marek
authors: M
authors: Niedziela
authors: Tim M
authors: TM
authors: Strom
authors: Martin
authors: M
authors: Fassnacht
authors: Luca
authors: L
authors: Persani
authors: Ralf
authors: R
authors: Paschke
mesh_terms: D000328:Adult; D000368:Aged; D020134:Catalytic Domain; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D011989:Receptors, Thyrotropin / Q000235:genetics; D012984:Software; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D011989:Receptors, Thyrotropin; C103523:EZH1 protein, human; D063151:Polycomb Repressive Complex 2; D019205:GTP-Binding Protein alpha Subunits, Gs