The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms.

Abstract

The development and progression of thyroid tumors are associated with phenotype-specific mutations of genes involved in growth control. Thyroid cell growth is controlled in part by the interaction of TSH with its receptor, with subsequent activation of the GTP-binding protein and its effector, adenylyl cyclase. The resulting increase in intracellular cAMP stimulates growth in thyrocytes. The TSH receptor (TSH-R) is a seven-transmembrane domain receptor. Intracellular domains of the TSH-R important for signal transduction and which may serve as targets for mutational activation have been defined. In addition, mutations at specific loci of the alpha-subunit of G-protein in human thyroid tumors have been described. We examined 92 benign and malignant neoplastic thyroid tissues for possible mutations of the intracytoplasmic domains of the TSH-R known to be involved in signal transduction and for mutations within the hot spots of Gs alpha. Screening was carried out by single strand conformation polymorphism (TSH-R) or denaturing gradient gel electrophoresis (Gs alpha) of polymerase chain reaction-amplified tumor DNA. No mutations were observed in the cytoplasmic domains of the TSH-R, except for a neutral base substitution in codon 460 (GCG [Ala]-->GCA [Ala]) in 3 tumors, which was also present in constitutional DNA from the affected individuals. A heterozygous mutation of codon 201 of Gs alpha (GGT [Arg]-CAT [His]) was observed in a nodule from an adenomatous goiter. In addition, a codon 227 mutation (CAG [Glu]-CAT [His]) was identified in a follicular adenoma. We conclude that mutational activation of the intracytoplasmatic domains of the TSH-R is not a significant mechanism of thyroid tumorigenesis, whereas putative activating mutations within exons 8 and 9 of Gs alpha occur infrequently in some benign follicular tumors.

WOMEN IN CANCER THEMATIC REVIEW: Thyroid-stimulating hormone in thyroid cancer: does it matter?

“…An argument against its involvement in tumour initiation is the lack of TSH receptor mutations interfering with signal transduction in thyroid carcinomas (Matsuo et al 1993). Furthermore, thyroid carcinomas can occur in patients with a range of serum TSH, including in those who take exogenous thyroid hormones and have suppressed serum TSH concentrations for treatment of other thyroid diseases (Satta et al 1993).…”

The association between serum TSH concentration and thyroid cancer

“…First, TSH receptor mutations in regions functionally associated with increased signal transduction do not commonly occur in thyroid carcinomas (Matsuo et al 1993). Second, in vitro studies have shown that other growth factors such as insulin-like growth factor-I (IGF-I) have been shown to be more potent in stimulating thyroid cancer growth (Derwahl et al 1999, Mazzaferri 2000, and TSH requires cooperation with insulin/IGF-1 to exert its proliferative effects (Kimura et al 2001).…”

The Genetics of the Thyroid Stimulating Hormone Receptor: History and Relevance

“…The 5th-6th TMDs (TM5-TM6) and the 3rd extracellular loop regions of the TSHR have most of the activating mutations. It is intriguing that the TSHR was thought of as a candidate oncogene for thyroid tumors, although structural studies did not support this view (79). However, Fournes et al (80) examined the oncogenic potential of a mutant hTSHR or Gsa expressed in rat FRTL-5 cells, and showed that only the mutant TSHR was able to induce neoplastic transformation, as demonstrated by growth in semi-solid medium and tumorigenesis in nude mice.…”