Thyrotropin receptor mutations and thyroid hyperfunctioning adenomas ten years after their first discovery: unresolved questions.
ABSTRACT Ten years after the first description of activating mutations in the thyroid stimulating hormone receptor (TSHR) gene in sporadic autonomous hyperfunctioning thyroid adenomas, there is general agreement in assigning a major pathogenic role of this genetic abnormality, acting via the constitutive activation of the cAMP pathway, in both the growth and functional characteristic of these tumours. From the beginning, however, the pathophysiological and clinical relevance of somatic TSHR mutations has been debated and some arguments still exist against a fully causative role of these mutations and the practical value of detecting these mutations for the diagnosis, treatment and prognosis of thyroid hot nodules. Some major issues will be examined herein, including (a) the frequency of TSHR alterations in various reports showing that the genetic abnormality underlying the pathogenesis of a substantial subset of thyroid tumours has yet to be identified; (b) the limitations of the present experimental models, which suggest greater caution in the interpretation of in vitro results; (c) the still unresolved question of absence of genotype-phenotype correlation. Clarification of these issues may hopefully provide new and useful tools for improving the clinical management of this disease.
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ABSTRACT: Evidence from in vitro studies or animal models has shown that TSH affects thyrocytes by thyroid-specific expression modulation. The objective of our study was to analyze the role of TSH in human thyroid gene expression in vivo. Thirty-nine normal thyroid tissues were collected at the same center. Patients were divided into two groups based on serum TSH levels: 17 with normal TSH levels (1-4 mU/liter; group 1) and 22 with TSH levels below 0.5 mU/liter (group 2). Intervention: Group 2 underwent thyroidectomy after suppressive L-T4 therapy. mRNA levels of thyroid genes such as sodium/iodide symporter (NIS), apical iodide transporter, pendrin, thyroglobulin, thyroperoxidase, TSH receptor, paired box transcription factor 8, and thyroid transcription factor-1 were evaluated by quantitative PCR. The reduction of TSH stimulation causes decreases in NIS and apical iodide transporter gene expression in normal tissues and more limited reductions in thyroglobulin, thyroperoxidase, and paired box transcription factor 8, but it has no significant effect on TSH receptor, pendrin, or thyroid transcription factor-1. Comparison of NIS levels in normal and nodular tissues from the same patient confirmed that it is differentially expressed in nodules only in the presence of normal TSH (P < 0.01). In patients with suppressed TSH, nodular NIS levels were similar to those in normal tissues. Our data represent the first demonstration in human thyroid tissues that TSH contributes to the regulation of thyrocyte differentiation by modulating thyroid gene levels. It exerts a particularly important effect on the transcription of NIS, which becomes very low after prolonged TSH suppression.Journal of Clinical Endocrinology & Metabolism 11/2005; 90(10):5692-7. · 6.43 Impact Factor
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ABSTRACT: Thyroid nodules are common, but only a small proportion harbour malignancy. Despite this, the frequency of thyroid cancer is on the increase and thyroid malignancy is the most common endocrine malignancy. Preoperative diagnosis is based on ultrasound and radionucleotide imaging as well as the fine-needle aspiration biopsy (FNAB). These biopsies yield a large proportion of indeterminate results due to inadequate material for cytological diagnosis, or due to the cytological similarity of FAs and follicular carcinomas. Recent advances in the understanding of the molecular pathogenesis of thyroid malignancy have led to the detection of characteristic genetic alterations in FNABs. This technology has the potential to increase the specificity of this test, combining cytological with genetic testing to reduce the number of indeterminate results, thereby reducing the number of thyroidectomies performed for benign disease. This review examines the evidence for the presence of the common genetic alterations in thyroid cancer and outlines the pathological and clinical correlations of these mutations. The practicality and utility of measuring these genetic alterations in FNAB specimens is also outlined as well as the potential for these tests to alter primary management and follow-up of patients with nodular thyroid disease. It is likely that a combination of molecular testing and cytological examination of FNAB specimens will prove to be the most efficient and specific method of diagnosing thyroid cancer preoperatively.ANZ Journal of Surgery 01/2010; 80(1-2):33-40. · 1.50 Impact Factor
Chapter: Molecular Biology of Thyroid Cancer[Show abstract] [Hide abstract]
ABSTRACT: There have been significant advances in our understanding of the molecular biology of thyroid cancer, and many of these studies have important clinical ramifications or applications to optimizing patient management. For example, the discovery of the germline mutation in the RET proto-oncogene that is responsible for hereditary medullary thyroid cancer has resulted in the ability to perform prophylactic thyroidectomy in at-risk individuals and more effective screening of at-risk family members, and the realization that genotype–phenotype associations are present. Genetic studies also provide a more precise estimate of tumor aggressiveness and identify individuals predisposed to having additional endocrine tumors (hyperparathyroidism and pheochromocytoma).12/2008: pages 97-110;