Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

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

In: Journal of Clinical Investigation, Vol. 126, No. 9, 01.09.2016, p. 3383-3388.

Research output: Contribution to journalArticlepeer-review

Harvard

Calebiro, D, Grassi, ES, Eszlinger, M, Ronchi, CL, Godbole, A, Bathon, K, Guizzardi, F, De Filippis, T, Krohn, K, Jaeschke, H, Schwarzmayr, T, Bircan, R, Gozu, HI, Sancak, S, Niedziela, M, Strom, TM, Fassnacht, M, Persani, L & Paschke, R 2016, 'Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas', Journal of Clinical Investigation, vol. 126, no. 9, pp. 3383-3388. https://doi.org/10.1172/JCI84894

APA

Calebiro, D., Grassi, E. S., Eszlinger, M., Ronchi, C. L., Godbole, A., Bathon, K., Guizzardi, F., De Filippis, T., Krohn, K., Jaeschke, H., Schwarzmayr, T., Bircan, R., Gozu, H. I., Sancak, S., Niedziela, M., Strom, T. M., Fassnacht, M., Persani, L., & Paschke, R. (2016). Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. Journal of Clinical Investigation, 126(9), 3383-3388. https://doi.org/10.1172/JCI84894

Vancouver

Author

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. / Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 9. pp. 3383-3388.

Bibtex

@article{d4d3a20488a2484a9d29e130a2f3bd31,
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.",
author = "Davide Calebiro and Grassi, {Elisa S.} and Markus Eszlinger and Ronchi, {Cristina L.} and Amod Godbole and Kerstin Bathon and Fabiana Guizzardi and {De Filippis}, Tiziana and Knut Krohn and Holger Jaeschke and Thomas Schwarzmayr and Rifat Bircan and Gozu, {Hulya Iliksu} and Seda Sancak and Marek Niedziela and Strom, {Tim M.} and Martin Fassnacht and Luca Persani and Ralf Paschke",
year = "2016",
month = sep,
day = "1",
doi = "10.1172/JCI84894",
language = "English",
volume = "126",
pages = "3383--3388",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "9",

}

RIS

TY - JOUR

T1 - Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

AU - Calebiro, Davide

AU - Grassi, Elisa S.

AU - Eszlinger, Markus

AU - Ronchi, Cristina L.

AU - Godbole, Amod

AU - Bathon, Kerstin

AU - Guizzardi, Fabiana

AU - De Filippis, Tiziana

AU - Krohn, Knut

AU - Jaeschke, Holger

AU - Schwarzmayr, Thomas

AU - Bircan, Rifat

AU - Gozu, Hulya Iliksu

AU - Sancak, Seda

AU - Niedziela, Marek

AU - Strom, Tim M.

AU - Fassnacht, Martin

AU - Persani, Luca

AU - Paschke, Ralf

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84987792301&partnerID=8YFLogxK

U2 - 10.1172/JCI84894

DO - 10.1172/JCI84894

M3 - Article

AN - SCOPUS:84987792301

VL - 126

SP - 3383

EP - 3388

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -