STRUCTURAL STUDIES OF THE THYROTROPIN RECEPTOR AND G(S)ALPHA IN HUMANTHYROID CANCERS - LOW-PREVALENCE OF MUTATIONS PREDICTS INFREQUENT INVOLVEMENT IN MALIGNANT TRANSFORMATION

The genes for either the TSH receptor (TSH-R) or the stimulatory guani ne nucleotide-binding protein subunit (G(s) alpha) can undergo somatic mutations in thyroid cells, leading to constitutive activation of ade nylyl cyclase and the formation of clonal hyperfunctioning thyroid ade nomas. Autonomously functioning thyroid adenomas are thought not to be common precursors of thyroid cancer. If this is the case, mutations o f the TSH-R or G(s) alpha would not be expected to be highly prevalent in thyroid carcinomas. In this paper we report the results of a scree n for structural defects in exon 10 of the TSH-R (which includes the w hole serpentine structure, but not the extracellular domain) and of G( s) alpha in 30 thyroid carcinomas. Five of these were from patients wi th functioning metastasis, as we hypothesized that if mutations of the se genes were to play a role in the progression to malignancy, they wo uld be more likely to manifest in thyroid cancers that retain unusual differentiated function (i.e. capable of synthesizing enough thyroid h ormone to render patients euthyroid or hyperthyroid after total thyroi dectomy). None of the 30 tumors had activating point mutations of G(s) alpha. Only 2 of 30 had somatic mutations of the TSH-R (codon 632: AC C to GCC, Thr to Ala; and ACC to ATC, Thr to Ile, respectively), the l atter in a patient with a thyroid hormone-producing follicular carcino ma. These results suggest that events leading to constitutive activati on of the adenylate cyclase signal transduction cascade are not a freq uent event in the progression toward differentiated thyroid carcinomas .