Structural studies of the thyrotropin receptor and Gs alpha in human thyroid cancers: low prevalence of mutations predicts infrequent involvement in malignant transformation.

Abstract

The genes for either the TSH receptor (TSH-R) or the stimulatory guanine nucleotide-binding protein subunit (Gs alpha) can undergo somatic mutations in thyroid cells, leading to constitutive activation of adenylyl cyclase and the formation of clonal hyperfunctioning thyroid adenomas. Autonomously functioning thyroid adenomas are thought not to be common precursors of thyroid cancer. If this is the case, mutations of the TSH-R or Gs alpha would not be expected to be highly prevalent in thyroid carcinomas. In this paper we report the results of a screen for structural defects in exon 10 of the TSH-R (which includes the whole serpentine structure, but not the extracellular domain) and of Gs alpha in 30 thyroid carcinomas. Five of these were from patients with functioning metastasis, as we hypothesized that if mutations of these genes were to play a role in the progression to malignancy, they would be more likely to manifest in thyroid cancers that retain unusual differentiated function (i.e. capable of synthesizing enough thyroid hormone to render patients euthyroid or hyperthyroid after total thyroidectomy). None of the 30 tumors had activating point mutations of Gs alpha. Only 2 of 30 had somatic mutations of the TSH-R (codon 632: ACC to GCC, Thr to Ala; and ACC to ATC, Thr to Ile, respectively), the latter in a patient with a thyroid hormone-producting follicular carcinoma. These results suggest that events leading to constitutive activation of the adenylate cyclase signal transduction cascade are not a frequent event in the progression toward differentiated thyroid carcinomas.

Role of the cAMP and MAPK pathways in the transformation of mouse 3T3 fibroblasts by a TSHR gene constitutively activated by point mutation

“…This activation may be higher in the 3T3/TSHR M623 cells. It is tempting to propose, taking into account however that our data have been obtained using murine ®broblasts, that the constitutively activated TSHR mutated genes detected by us and others in dierentiated thyroid carcinomas (Russo et al, 1995b;Spambalg et al, 1996) have played a similar role in the development of these tumors, acting as an oncogene through the activation of both the cAMP and MAPK pathways. Following a multistep model for thyroid carcinogenesis (SaõÈ d et al, 1994), it can be postulated that a constitutive activation of the cAMP pathway may provide a growth advantage to a clone(s) already transformed by an activated Ras through the MAPK pathway and partially abolishing, through an unknown mechanism(s), the dierentiation induced in the transformed thyrocytes by cAMP.…”

“…These observations implicate the G as protein subunit and its linked cell surface TSHR in hyperproliferative diseases, including perhaps cancer. In this context it is interesting to point out that TSHR mutations were also described by us in codon 623 changing an Ala to a Ser (GCC?TCC) and Spambalg et al in codon 632 changing a Thr to Ala or Ile (ACC?GCC or ACC?ATC), in some dierentiated thyroid carcinomas (Russo et al, 1995b;Spambalg et al, 1996;Sua rez et al, 1991). The carcinomas studied in our laboratory presented increased basal levels of cAMP and a poor response to TSH, mimicking the phenotype of a hyperfunctionning adenoma (Russo et al, 1995b;Sua rez et al, 1991).…”

“…The carcinomas studied in our laboratory presented increased basal levels of cAMP and a poor response to TSH, mimicking the phenotype of a hyperfunctionning adenoma (Russo et al, 1995b;Sua rez et al, 1991). Unfortunately, such parameters were not analysed in the carcinomas studied by Spambalg et al (1996). These latter data raises the question of whether, the stimulation of the cAMP pathway was alone responsable for the highly agressive and malignant phenotype showed by our thyroid carcinomas.…”

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

“…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.…”

Follicular Variant of Papillary Thyroid Carcinoma Presenting as Toxic Nodule in an Adolescent: Coexistent Polymorphism of the TSHR and Gsα Genes

“…Germline, and therefore inheritable, TSHR gene mutations occur in familial and sporadic nonautoimmune hyperthyroidism (20,21). Somatic mutations of the TSHR gene have also been described in cases of hyperfunctioning carcinomas (12,13,(22)(23)(24)(25)(26)(27), and there is evidence for a role of TSHR and/or Gsa mutations in thyroid tumorigenesis (28)(29)(30)(31).…”