Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Research output: Contribution to journalArticle

Authors

  • Elisa S. Grassi
  • Markus Eszlinger
  • Amod Godbole
  • Kerstin Bathon
  • Fabiana Guizzardi
  • Tiziana De Filippis
  • Knut Krohn
  • Holger Jaeschke
  • Thomas Schwarzmayr
  • Rifat Bircan
  • Hulya Iliksu Gozu
  • Seda Sancak
  • Marek Niedziela
  • Tim M. Strom
  • Martin Fassnacht
  • Luca Persani
  • Ralf Paschke

External organisations

  • Rudolf Virchow Center
  • Istituto Auxologico Italiano
  • Leipzig Research Center for Early Child Development
  • University of Leipzig
  • Technische Universitat Munchen
  • Namik Kemal University
  • Marmara University
  • Fatih Sultan Mehmet Training and Educational Hospital
  • Poznan University of Medical Sciences
  • University of Würzburg
  • Università degli Studi di Milano and oINFN-Milan
  • University of Calgary

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.

Details

Original languageEnglish
Pages (from-to)3383-3388
Number of pages6
JournalJournal of Clinical Investigation
Volume126
Issue number9
Early online date8 Aug 2016
Publication statusPublished - 1 Sep 2016

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