Sensitive Sequencing Analysis Suggests Thyrotropin Receptor and Guanine Nucleotide-Binding Protein G Subunit Alpha as Sole Driver Mutations in Hot Thyroid Nodules

Stephenson, Alexandra; Eszlinger, Markus; Stewardson, Paul; McIntyre, John B.; Boesenberg, Eileen; Bircan, Rıfat; Sancak, Seda; Gözü, Hülya Ilıksu; Ghaznavi, Sana; Krohn, Knut; Paschke, Ralf

doi:10.1089/thy.2019.0648

Cited by 11 publications

(11 citation statements)

References 31 publications

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“…In this series, all of the nodules with TSHR , GNAS , or EZH1 mutations were observed clinically and approximately half are known to be stable 1 to 3 years after the FNA. It is now accepted that up to 85% of histologically diagnosed hyperplastic thyroid nodules, especially autonomous toxic thyroid adenomas, harbor TSHR , GNAS , or EZH1 mutations 12,14,27 . Most of the patients with apparent AFTNs in this study were euthyroid, consistent with prior reports 15 .…”

Section: Discussionsupporting

confidence: 90%

“…It is now accepted that up to 85% of histologically diagnosed hyperplastic thyroid nodules, especially autonomous toxic thyroid adenomas, harbor TSHR, GNAS, or EZH1 mutations. 12,14,27 Most of the patients with apparent AFTNs in this study were euthyroid, consistent with prior reports. 15 TSHR, GNAS, or EZH1 mutations were only rarely reported in thyroid malignancies and usually in nodules with either coexisting mutations (PAX8-PPARG fusion) or with higher TSHR, GNAS, or EZH1 mutant allele frequency.…”

Section: Cancer Cytopathology October 2021supporting

confidence: 91%

“…Specifically, mutations of thyroid-stimulating hormone receptor (TSHR), guanine nucleotide-binding protein G subunit alpha (GNAS), or enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1), sometimes with overexpression of solute carrier family 5 member 5 (SLC5A5)/sodium (Na)iodide symporter (NIS) were identified in the majority of AFTNs. [12][13][14][15][16][17] Other genetic differences between oncocytic and nononcocytic thyroid neoplasms have been established. 4 For instance, oncocytic thyroid neoplasms typically lack BRAF V600E mutations and BRAF-like alterations (eg, RET/PTC rearrangements).…”

Section: Introductionmentioning

confidence: 99%

“…Although GH‐CNA provides molecular confirmation of oncocytic neoplasia, genetic alterations characteristic of AFTNs can now be identified by molecular testing of FNAs, also. Specifically, mutations of thyroid‐stimulating hormone receptor ( TSHR ), guanine nucleotide‐binding protein G subunit alpha ( GNAS ), or enhancer of zeste 1 polycomb repressive complex 2 subunit ( EZH1 ), sometimes with overexpression of solute carrier family 5 member 5 ( SLC5A5 )/sodium (Na)‐iodide symporter (NIS) were identified in the majority of AFTNs 12‐17 …”

Section: Introductionmentioning

confidence: 99%

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Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

Landau

Nikiforov

Ohori

et al. 2021

Cancer Cytopathology

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BACKGROUND: Some thyroid nodules cytologically presenting as follicular neoplasm, Hürthle cell (Oncocytic) type (FNHCT), are not oncocytic tumors and represent autonomously functioning thyroid nodules (AFTNs) with TSHR, GNAS, and EZH1 mutations or oncocytic metaplasia. A to be defined subset of FNHCT harbors genome haploidisationtype DNA copy number alterations (GH-CNA). Molecular profiling of FNHCT may distinguish oncocytic neoplasms from its mimics. METHODS: Consecutive fine-needle aspirates of 180 thyroid nodules over 37 months diagnosed as FNHCT and tested by ThyroSeq v3 were identified. Histologic follow-up was available for 79 of 180 nodules (44%). RESULTS:No molecular alterations were found in 76 of 180 nodules (42%), of which 15 were resected (oncocytic metaplasia, n = 7; follicular oncocytic adenoma, n = 8). Of nodules followed without surgery, 17 of 101 (17%) showed TSHR, EZH1, and GNAS mutations of AFTNs. Papillary thyroid carcinoma was identified by BRAF V600E (n = 2) and hyalinizing trabecular adenoma by PAX8-GLIS3 (n = 1). GH-CNA alone was detected in 42 of 180 FNHCT nodules (23%), of which 29 were resected and histologically diagnosed as follicular oncocytic neoplasms. All remaining resected nodules were histologically proven oncocytic neoplasms: 1) RAS-like alterations without GH-CNA (n = 25) and 2) TERT and/or TP53 mutations co-occurring with GH-CNA (n = 6), including anaplastic thyroid carcinoma arising from follicular oncocytic carcinoma with TP53, TERT mutations with GH-CNA (n = 2). CONCLUSIONS: A proportion of FNHCT nodules are AFTNs and oncocytic metaplasias, which can be suspected based on characteristic mutations or lack of alterations on molecular testing. Among resected FNHCTs, GH-CNAs characterize approximately half of histologically confirmed follicular oncocytic neoplasms.

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Section: Discussionsupporting

confidence: 90%

Section: Cancer Cytopathology October 2021supporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

Landau

Nikiforov

Ohori

et al. 2021

Cancer Cytopathology

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“…A less common form of hyperthyroidism is nonautoimmune hyperthyroidism (NAH) ( 1 ). There are three subcategories, that is, hot nodules caused by somatic thyroid-stimulating hormone receptor (TSHR) mutation ( 2 ), sporadic TSHR germline mutation (SNAH) ( 3 ) and inherited TSHR germline mutations (familial, FNAH). A description of dominantly transmitted nonautoimmune hyperthyroidism was first published in 1982, and the molecular etiology was described in 1994 ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Report of a family with three generations of undiagnosed familial nonautoimmune hyperthyroidism

Stephenson

Punjwani

Eszlinger

et al. 2021

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary Familial nonautoimmune hyperthyroidism (FNAH) is rare and occurs due to a constitutively activating thyroid-stimulating hormone receptor (TSHR) germline mutation. Forty-one families with FNAH have been reported so far. In the study, 17 of 41 families were not diagnosed with FNAH until three generations or more were described with hyperthyroidism. We report a case of FNAH diagnosed in the third generation. The index patient was diagnosed with hyperthyroidism at age 3. Large fluctuations in thyroid hormone levels occurred during anti-thyroid drug treatment, and he developed a goiter. The patient’s mother had similar history, requiring two surgical interventions and radioiodine treatment. The younger brother of the index patient did not experience large thyroid hormone level fluctuations, nor increased thyroid growth. A heterozygous TSHR c.1357A>G mutation, resulting in a M453V amino acid exchange, was detected in all three patients leading to FNAH diagnosis, with complete genotype–phenotype segregation. Based on Sorting intolerant from tolerant (SIFT) and PolyPhen2 scores of 0.01 and 0.99, respectively, an effect on protein function can be assumed. As illustrated by this family with FNAH, total thyr oidectomy is necessary for patients with nonautoimmune hyperthyroidism. Development of goiter is common, anti-thyroid drug treatment is often difficult, and remission of hyperthyroidism does not occur after discontinuation of anti-thyroid drug treatment. Thus, early diagnosis and appropriate treatment of FNAH is necessary to avoid predictable, unnecessary complications and further surgical interventions. Learning points In the study, 19/42 cases of familial nonautoimmune hyperthyroidism (FNAH), including the reported case, were not diagnosed as FNAH until the third generation; this lead to suboptimal treatment and frequent relapses of nonautoimmune hyperthyroidism (NAH). Detection of thyroid-stimulating hormone receptor (TSHR) mutations in patients with suspected FNAH to confirm diagnosis is essential to ensure proper treatment for the patient and further affected family members. NAH will persist without proper treatment by total thyroidectomy. Symptoms and age of onset may vary between family members All family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.

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Thyroid Pathology

Kurian

2024

Thyroid Radiofrequency Ablation

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Sensitive Sequencing Analysis Suggests Thyrotropin Receptor and Guanine Nucleotide-Binding Protein G Subunit Alpha as Sole Driver Mutations in Hot Thyroid Nodules

Cited by 11 publications

References 31 publications

Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

Report of a family with three generations of undiagnosed familial nonautoimmune hyperthyroidism

Thyroid Pathology

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