Calebiro Davide, Grassi Elisa S, Eszlinger Markus, Ronchi Cristina L, Godbole Amod, Bathon Kerstin, Guizzardi Fabiana, de Filippis Tiziana, Krohn Knut, Jaeschke Holger, Schwarzmayr Thomas, Bircan Rifat, Gozu Hulya Iliksu, Sancak Seda, Niedziela Marek, Strom Tim M, Fassnacht Martin, Persani Luca, Paschke Ralf
J Clin Invest. 2016 Sep 1;126(9):3383-8. doi: 10.1172/JCI84894. Epub 2016 Aug 8.
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.
自主性甲状腺腺瘤（ATA）是甲状腺功能亢进症的常见病因。在大约70%的ATA中发现了编码促甲状腺激素受体（TSHR）或Gs蛋白α亚基（GNAS）的基因突变。目前尚不清楚其他基因的参与情况以及其余病例的发病机制。在此，我们对19例ATA及其配对的正常DNA样本进行了全外显子组测序，在zeste同源物1（EZH1）基因的增强子中鉴定出一个复发性热点突变（c.1712A>G；p.Gln571Arg），该基因编码多梳复合体的一个催化亚基。在一个独立队列中的靶向筛查证实，该突变在ATA中高频出现（27%）。EZH1突变与cAMP信号通路基因中已知的（TSHR、GNAS）或推测的（腺苷酸环化酶9 [ADCY9]）改变密切相关。此外，功能研究表明，p.Gln571Arg EZH1突变导致组蛋白H3三甲基化增加和甲状腺细胞增殖增加。总之，本研究揭示EZH1热点突变是ATA中第二常见的基因改变。EZH1与TSHR突变之间的关联提示了这些肿瘤发病机制的双打击模型，即cAMP信号通路的组成性激活与EZH1突变共同作用诱导甲状腺细胞过度增殖。
