Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Palos-Paz, Fernando; Perez-Guerra, Oscar; Cameselle-Teijeiro, Jorge F; Rueda-Chimeno, C; Barreiro-Morandeira, Francisco; Lado-Abeal, Joaquín; Vilar, D; Argüeso, Rosa; Barca, Olga; Botana, Manuel; Cabezas-Agrícola, José Manuel; Catalina, Pablo Fernández; Gerpe, Lourdes Domínguez; Fernandez, T; Mato, Anthony R.; Nuno, Asami; Lama, Manuel; Victoria, Berta

doi:10.1530/eje-08-0313

Cited by 64 publications

(44 citation statements)

References 55 publications

(53 reference statements)

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“…Since we did not find any GNAS1 mutation in 31 GEP-NETs, it may be assumed that this mutation is rarely involved in the development of this kind of tumors. Our findings contrast with reports which showed a detectable frequency of GNAS1 mutation in other neuroendocrine tumors, for example 40% GH-secreting pituitary tumors presented GNAS1 mutations [36] and toxic thyroid adenomas -4.71% GNAS1 mutations [37]. The mutational spectrum of GNAS1 seems also to be different in patients with pseudohypoparathyroidism [38].…”

Section: Discussioncontrasting

confidence: 99%

GNAS1 mutation analysis in gastrointestinal tumors

Walther

Chen³

et al. 2014

Folia Histochem Cytobiol.

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GNAS1 codes for a part of the a-stimulatory subunit (Gsa) of the G protein. Mutation of GNAS1 has been frequently found in myxoid soft tissues, however, in gastrointestinal tumors, little is known about the mutation status of GNAS1. The aim of the study was to analyze the occurrence of GNAS1 mutations in different gastrointestinal, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and colorectal tumors. Mutation status of GNAS1 exon 8 was analyzed in one hundred thirty-five formalin-fixed, paraffin-embedded (FFPE) gastrointestinal tumor samples including 45 tubular-villous adenomas, 11 tubular adenomas, 6 villous adenomas, 10 hyperplastic gastric polyps, 31 GEP-NETs and 32 colorectal adenocarcinomas by using polymerase chain reaction (PCR) and direct sequencing. Five GNAS1 mutations were found in 2 tubular-villous adenomas, 2 villous adenomas and 1 colorectal adenocarcinoma. No mutations were detected in the tubular adenomas, the hyperplastic gastric polyps or GEP-NETs. GNAS1 mutation is not a frequent molecular event in GEP-NETs or hyperplastic gastric polyps. The study confirms the presence of GNAS1 mutations in colon tumors with villous differentiation. (Folia Histochemica et Cytobiologica 2014, Vol. 52, No. 2, 90-95)

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Section: Discussioncontrasting

confidence: 99%

GNAS1 mutation analysis in gastrointestinal tumors

Walther

Chen³

et al. 2014

Folia Histochem Cytobiol.

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“…Mutations in this gene are found in w33% of GH-secreting pituitary tumors (Vallar et al 1987, Barlier et al 1998, but are uncommon in thyroid tumors, although there have been case reports of these mutations in congenital autonomous goiters (Weinstein et al 2001, Palos-Paz et al 2008. By contrast, activating mutations of the TSH receptor, which signals through GNAS1, have been described both in nodules and in congenital cases (Parma et al 1993, 1997, Russo et al 1995, Fuhrer et al 1997a,b, Cetani et al 1999, Postiglione et al 2002, Palos-Paz et al 2008.…”

Section: Relation To Human Disease (And Endocrine Cancer)mentioning

confidence: 99%

Mouse models of altered protein kinase A signaling

Kirschner¹,

Yin²,

Jones³

et al. 2009

Endocrine-Related Cancer

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Protein kinase A (PKA) is an evolutionarily conserved protein which has been studied in model organisms from yeast to man. Although the cAMP-PKA signaling system was the first mammalian second messenger system to be characterized, many aspects of this pathway are still not well understood. Owing to findings over the past decade implicating PKA signaling in endocrine (and other) tumorigenesis, there has been renewed interest in understanding the role of this pathway in physiology, particularly as it pertains to the endocrine system. Because of the availability of genetic tools, mouse modeling has become the pre-eminent system for studying the physiological role of specific genes and gene families as a means to understanding their relationship to human diseases. In this review, we will summarize the current data regarding mouse models that have targeted the PKA signaling system. These data have led to a better understanding of both the complexity and the subtlety of PKA signaling, and point the way for future studies, which may help to modulate this pathway for therapeutic effect.

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“…Both of these mutations are relatively rare. In iodine-deficient region, either codon 281 or 568 mutations are found in 6 out of 52 TSHR mutations (11.5%), including S281N in 1 case, S281T in 1 case and I568T in 4 cases [10]. A report from Japan, iodine sufficient region, these mutations are found in 2 out of 22 TSHR mutations (9.1%), including S281N in 1 case and I568T in 1 case [9].…”

Section: Casementioning

confidence: 90%

“…The majority of the mutations are located in transmembrane helix (TMH) 6 and TMH 2, and several mutations are located in intracellular loop (ICL) 3 [10,11]. These domains are reported to have an important role in the basal activation of cAMP production.…”

mentioning

confidence: 99%

Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas

et al. 2012

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Seven transmembrane (7TM) receptors play important roles in various biologic signal transduction systems, including endocrine and neural regulation. Mutations in these receptors cause various health disorders. Gain-of-function mutations in the thyroid stimulating hormone receptor (TSHR) gene result in hyperthyroidism [1]. In addition to germ-line mutations, somatic mutations of the TSHR gene and the adenylate cyclase-stimulating G α protein (GNAS) gene are responsible for toxic adenoma and toxic multinodular Abstract. Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodinedeficient regions, but they are relatively rare in iodine-sufficient regions, including Japan. Constitutive activating mutations of the thyroid stimulating hormone receptor (TSHR) gene and adenylate cyclase-stimulating G α protein (GNAS) gene are frequent in these thyrotoxic disorders. Here we report two cases of rare TSHR gene mutations in Japanese thyrotoxicosis patients. In Case 1, we observed multiple toxic nodules with thyrotoxicosis, and in Case 2, we detected a solitary toxic nodule in an 8-year-old girl. In both cases, ultrasonography showed thyroid nodules and scintigraphy revealed increased uptake. Total thyroidectomy was performed for Case 1 and a hemi-thyroidectomy was performed for Case 2. Genetic analysis of the resected tissues revealed an I568F mutation in Case 1 and a S281I mutation in the TSHR gene in Case 2. The I568F mutation was located in the second extracellular loop, and the S281I mutation was located in the N-terminal extracellular domain of the TSH receptor. In Case 1, the mutation was restricted to the largest nodule, and was not detected in other functioning nodules or non-nodule thyroid tissue. Bi-allelic expression of the TSHR gene was confirmed by reverse transcription-polymerase chain reaction in both tumors. Both the I568F and S281I mutations were studied previously in vitro, and were revealed to cause basal activation of the protein kinase A pathway. Case 1 represents the second reported case of an I568F mutation and Case 2 represents the third reported case of an S281I mutation.

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Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Cited by 64 publications

References 55 publications

GNAS1 mutation analysis in gastrointestinal tumors

GNAS1 mutation analysis in gastrointestinal tumors

Mouse models of altered protein kinase A signaling

Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas

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