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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 ? 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.

SUBMITTER: Calebiro D

PROVIDER: S-EPMC5004945 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Calebiro Davide D Grassi Elisa S ES Eszlinger Markus M Ronchi Cristina L CL Godbole Amod A Bathon Kerstin K Guizzardi Fabiana F de Filippis Tiziana T Krohn Knut K Jaeschke Holger H Schwarzmayr Thomas T Bircan Rifat R Gozu Hulya Iliksu HI Sancak Seda S Niedziela Marek M Strom Tim M TM Fassnacht Martin M Persani Luca L Paschke Ralf R

The Journal of clinical investigation 20160808 9

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 homolo ...[more]

PMID: 27500488

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Project description:ImportanceLinear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date.ObjectiveTo identify genetic mutations associated with linear porokeratosis.Design, setting, and participantsPaired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis.Interventions or exposuresWhole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions.Main outcomes and measuresGermline and somatic genomic characteristics of participants with linear porokeratosis.ResultsOf the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift).Conclusions and relevanceOur findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

Dataset Information

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

Publications

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

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