Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Calebiro, Davide; Grassi, Elisa; Eszlinger, Markus; Ronchi, Cristina L.; Godbole, Amod; Bathon, Kerstin; Guizzardi, Fabiana; Filippis, Tiziana de; Krohn, Knut; Jaeschke, Holger; Schwarzmayr, Thomas; Bircan, Rıfat; Gözü, Hülya Ilıksu; Sancak, Seda; Niedziela, Marek; Strom, Tim M.; Fassnacht, Martin; Persani, Luca; Paschke, Ralf

doi:10.1172/jci84894

Cited by 73 publications

(59 citation statements)

References 20 publications

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“…TG gene encodes thyroglobulin that is produced predominantly in the thyroid gland and plays essential roles for synthesis and storage of thyroid hormones [22]. Somatic TG mutations have been reported in autonomous thyroid adenoma and PTC [23, 24] and all TG mutations identified in this study were validated as somatic using Sanger sequencing (Figure S2). Functionally, however, it remains uncertain whether TG mutation is causally implicated in thyroid tumorigenesis.…”

Section: Resultsmentioning

confidence: 71%

Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma

et al. 2016

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Follicular thyroid adenoma (FTA) precedes follicular thyroid carcinoma (FTC) by definition with a favorable prognosis compared to FTC. However, the genetic mechanism of FTA to FTC progression remains unknown. For this, it is required to disclose FTA and FTC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of 14 FTAs and 13 FTCs, which exhibited previously-known gene mutations (NRAS, HRAS, BRAF, TSHR and EIF1AX) and copy number alterations (CNAs) (22q loss and 1q gain) in follicular tumors. In addition, we found eleven potential cancer-related genes with mutations (EZH1, SPOP, NF1, TCF12, IGF2BP3, KMT2C, CNOT1, BRIP1, KDM5C, STAG2 and MAP4K3) that have not been reported in thyroid follicular tumors. Of note, FTA genomes showed comparable levels of mutations to FTC in terms of the number, sequence composition and functional consequences (potential driver mutations) of mutations. Analyses of evolutionary ages using somatic mutations as molecular clocks further identified that FTA genomes were as old as FTC genomes. Whole-transcriptome sequencing did not find any gene fusions with potential significance. Our data indicate that FTA genomes may be as old as FTC genomes, thus suggesting that follicular thyroid tumor genomes during the transition from FTA to FTC may stand stable at genomic levels in contrast to the discernable changes at pathologic and clinical levels. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful for the molecular diagnosis and therapeutics of follicular tumor patients.

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Section: Resultsmentioning

confidence: 71%

Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma

et al. 2016

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“…In addition, we tested selected nodules for EZH1 mutation Q571R which has been recently described as a second hit in nodules with TSHR or GNAS mutations and is believed to cooperate to induce the increased proliferation of thyroid cells . We observed EZH1 mutation in 2 of 4 of thyroid carcinomas carrying TSHR mutations, but in neither of 2 benign nodules which also had relatively high allelic frequency TSHR mutations.…”

Section: Discussionmentioning

confidence: 89%

“…The presence of >50 high quality reads crossing the fusion point of the transcript was required to consider the test positive for a gene fusion. In addition, testing for the hot spot EZH1 mutation Q571R recently reported to coexist with TSHR mutations in hyperfunctioning nodules was performed using Sanger sequencing in cases with high allelic frequency of TSHR mutations in a limited number of cases where residual DNA was available …”

Section: Methodsmentioning

confidence: 99%

Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid‐stimulating hormone receptor gene mutations

Mon

Riedlinger

Abbott

et al. 2018

Diagnostic Cytopathology

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“…PTEN and PIK3CA mutations also occur in 5% of FA and up to 10% of FTC . Hyperfunctioning FA has mutations in TSHR , GNAS and EZH1 genes . EZH1 mutations also occur in Hürthle cell adenoma and minimally invasive FTC .…”

Section: Genetic Profiles and Molecular Diagnosis Of Thyroid Tumorsmentioning

confidence: 99%

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

Kakudo

Bychkov

Bai

et al. 2018

Pathology International

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Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Cited by 73 publications

References 20 publications

Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma

Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma

Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid‐stimulating hormone receptor gene mutations

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

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