A Phe 486 Thyrotropin Receptor Mutation in an Autonomously Functioning Follicular Carcinoma that was Causing Hyperthyroidism

Camacho, Pauline M.; Gordon, Donald L.; Chiefari, Eusebio; Yong, Sherri; DeJong, Steven; Pitale, Shailesh; Russo, Diego

doi:10.1089/thy.2000.10.1009

Cited by 60 publications

(40 citation statements)

References 17 publications

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“…In addition, to date, somatic TSHR mutations have been reported in nine differentiated thyroid carcinomas, five of which mimicked the phenotype of toxic thyroid nodules (Russo et al 1995, 1997, 1999, Spambalg et al 1996, Camacho et al 2000, Mircescu et al 2000. We describe the first patient with metastasising toxic follicular thyroid cancer, harbouring two different somatic TSHR mutations.…”

Section: Introductionmentioning

confidence: 78%

Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

Führer¹,

Tannapfel²,

Sabri³

et al. 2003

Endocrine-Related Cancer

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In a 59-year-old patient, thyroid follicular cancer was diagnosed in two right-sided toxic thyroid nodules, which had presented clinically as unilateral thyroid autonomy. In addition, the patient had histologically proven lung metastases of thyroid cancer; however, these failed to exhibit iodine uptake and were resistant to radioiodine treatment. The functional activity of the thyroid nodules prompted us to screen for TSH receptor (TSHR) mutations, and the histological diagnosis of follicular carcinoma led us to search for the PAX8-PPARγ1 rearrangement and mutations in the ras genes. Each thyroid nodule harboured a different TSHR mutation (large nodule, Asp633Tyr; small nodule, Phe631Ile). Presence of both mutations in one sample suggestive of local invasion of a thyroid carcinoma could not be demonstrated, although several specimens from different nodule locations were screened. Only the wild-type TSHR sequence was identified in the histologically normal left thyroid lobe, and no genetic alterations were found in the other investigated genes. No TSHR mutations were detected in the pulmonary metastases. This is the first case report of a patient with toxic follicular thyroid carcinoma harbouring two different TSHR mutations and presenting with non-functional lung metastases.

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Section: Introductionmentioning

confidence: 78%

Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

Führer¹,

Tannapfel²,

Sabri³

et al. 2003

Endocrine-Related Cancer

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“…Nevertheless, some cases of thyroid carcinoma presenting as 'hot' thyroid nodules have been described (Russo et al 1997, Camacho et al 2000, Mircescu et al 2000, Gozu et al 2004, Majima et al 2005, Niepomniszcze et al 2006.…”

Section: Introductionmentioning

confidence: 99%

“…As in benign autonomously functioning thyroid nodules, mutations in either the TSH receptor (TSHR) gene, or the adenylate cyclasestimulating G alpha protein (GNAS1) gene that activates the cAMP cascade, have been detected in a small number of thyroid carcinomas (Russo et al 1995, Spambalg et al 1996, Collins et al 2003, with a handful of those being autonomously hyperfunctioning thyroid carcinomas (Russo et al 1997, Camacho et al 2000, Mircescu et al 2000, Collins et al 2003, Fuhrer et al 2003, Gozu et al 2004, Niepomniszcze et al 2006. Chronic cAMP stimulation may contribute, under certain conditions, to tumor progression (Ludgate et al 1999), although it does not seem sufficient for malignant transformation of thyroid follicular cells, and other genetic alterations are probably required to achieve cancer development (Matsuo et al 1993, Russo et al 1995, Spambalg et al 1996, Ludgate et al 1999, Collins et al 2003, Sobrinho-Simões et al 2008.…”

Section: Introductionmentioning

confidence: 99%

Identification of a paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARγ) rearrangement mosaicism in a patient with an autonomous functioning follicular thyroid carcinoma bearing an activating mutation in the TSH receptor

Lado-Abeal¹,

Celestino²,

Bravo³

et al. 2010

Endocrine-Related Cancer

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Our main objective was to search for mutations in candidate genes and for paired box gene 8-peroxisome proliferator-activated receptor gamma (PAX8-PPARg) rearrangement in a well-differentiated angioinvasive follicular thyroid carcinoma (FTC) causing hyperthyroidism. DNA and RNA were extracted from the patient's thyroid tumor, as well as 'normal' thyroid tissue, and from peripheral blood lymphocytes (PBLs) of the patient, her daughter, and two siblings. Nuclear isolation was extracted from the patient's tumor, 'normal' thyroid tissue, PBLs, and uterine leiomyoma tissue. TSH receptor (TSHR ), RAS, and BRAF genes were sequenced. We searched for PAX8-PPARg in thyroid, PBL, and uterine leiomyoma samples from the patient and family members. Proliferative effects of detected mutants on non-transformed human thyrocytes cultures. An activating TSHR mutation, M453T, was detected in the tumor. PAX8 (exons 1-8C10 )-PPARg was found in all tested patient's tissues. A second rearrangement, PAX8 (exons 1-8 )-PPARg, was detected in the patient's normal thyroid tissue. Under deprived medium condition, co-transfection of PAX8-PPARg and TSHR-M453T dramatically increased the number of thyrocytes, an effect that it was not observed with TSHR wild-type (WT); under complete medium conditions, co-transfection of PAX8-PPARg with either TSHR-M453T or TSHR-WT inhibited cell proliferation. We report a patient with hyperthyroidism due to a FTC bearing an activating TSHR mutation and PAX8-PPARg rearrangements. PAX8-PPARg was present as a mosaicism affecting tissues from endodermal and mesodermal origin. PAX8-PPARg and TSHR-M453T inhibited or promoted thyrocyte proliferation depending on medium conditions. The activating TSHR mutation could promote in vivo FTC development in PAX8-PPARg-positive thyrocytes under poor blood supply with deprivation of growth factors but restraint the tumor growth when growth factors are supplied.

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“…A list of TSHR mutants may be found at <http://www.uni-leipzig.de/innere/tshr> and we have updated it in table 1. Spontaneous activating mutations of the TSHR gene appear at the onset of autonomous functioning thyroid adenomas (116,117) and more rarely of thyroid carcinomas (118)(119)(120)(121)(122)(123)(124). Somatic mutations cause autonomous nodules and germ-line mutations cause congenital hyperthyroidism and hereditary non-autoimmune toxic thyroid hyperplasia.…”

Section: The Tshr Gene Is Highly Susceptible To Constitutively Activamentioning

confidence: 99%

TSH signalling and cancer

García-Jiménez

Santisteban

2007

Arq Bras Endocrinol Metab

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Thyroid cancers are the most frequent endocrine neoplasms and mutations in the thyrotropin receptor (TSHR) are unusually frequent. Here we present the state-of-the-art concerning the role of TSHR in thyroid cancer and discuss it in light of the cancer stem cell theory or the classical view. We briefly review the gene and protein structure updating the cancer related TSHR mutations database. Intriguingly, hyperfunctioning TSHR mutants characterise differentiated cancers in contrast to undifferentiated thyroid cancers which very often bear silenced TSHR. It remains unclear whether TSHR alterations in thyroid cancers play a role in the onset or they appear as a consequence of genetic instability during evolution, but the presence of functional TSHR is exploited in therapy. We outline the signalling network build up in the thyrocyte between TSHR/PKA and other proliferative pathways such as Wnt, PI3K and MAPK. This network's integrity surely plays a role in the onset/evolution of thyroid cancer and needs further research. Lastly, future investigation of epigenetic events occurring at the TSHR and other loci may give better clues for molecular based therapy of undifferentiated thyroid carcinomas. Targeted demethylating agents, histone deacetylase inhibitors combined with retinoids and specific RNAis may help treatment in the future. RESUMOSinalização de TSH e Câncer. Os cânceres de tiróide são as neoplasias endócrinas mais frequentes e as mutações no receptor de tirotrofina (TSHR) são incomumente frequentes. Nesta revisão nós apresentamos o "estado da arte" com relação ao papel do TSHR no câncer de tiróide e o discutimos à luz da teoria da célula matriz do câncer ou a visão clássica. Revisamos brevemente a estrutura do gene e da proteína, atualizando a base de dados das mutações do TSHR relacionadas ao câncer. Curiosamente, mutações do TSHR com hiperfunção caracterizam cânceres diferenciados, em contraste com os cânceres de tiróide indiferenciados, os quais muito comumente mostram TSHR silenciados. Permanece obscuro se as alterações do TSHR em cânceres de tiróide têm algum papel no surgimento ou se elas aparecem como conseqüência da instabilidade genética durante seu desenvolvimento, mas a presença de TSHR funcional é explorada na terapia. Nós delineamos a rede de sinalizacão desenvolvida no tirócito entre TSHR/PKA e outras vias proliferativas como a Wnt, PI3k e MAPK. A integridade desta rede certamente tem um papel no surgimento/evolução do câncer de tiróide e necessita de novas pesquisas. Finalmente, novas investigacões sobre os eventos epigenéticos que ocorrem no TSHR e outros locais poderão trazer novas informações para uma terapia de base molecular nos carcinomas indiferenciados de tiróide. Agentes demetilantes direcionados, inibidores da histona-deacetilase, combinados com retinóides e RNAs específicos poderão auxiliar no tratamento futuro.

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A Phe 486 Thyrotropin Receptor Mutation in an Autonomously Functioning Follicular Carcinoma that was Causing Hyperthyroidism

Cited by 60 publications

References 17 publications

Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

Identification of a paired box gene 8–peroxisome proliferator-activated receptor gamma (PAX8–PPARγ) rearrangement mosaicism in a patient with an autonomous functioning follicular thyroid carcinoma bearing an activating mutation in the TSH receptor

TSH signalling and cancer

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