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.
Researchers 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.
For more information
Journal of Clinical Investigation
Recurrent EZH1 mutations are a second hit in
autonomous thyroid adenomas
Davide Calebiro, Elisa S. Grassi, Markus Eszlinger,
Cristina L. Ronchi, 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, and Ralf
Paschke.
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