THE THYROTROPIN RECEPTOR (TSH-R) IS NOT AN ONCOGENE FOR THYROID-TUMORS - STRUCTURAL STUDIES OF THE TSH-R AND THE ALPHA-SUBUNIT OF G(S) IN HUMAN THYROID NEOPLASMS

The development and progression of thyroid tumors are associated with phenotype-specific mutations of genes involved in growth control. Thyr oid cell growth is controlled in part by the interaction of TSH with i ts receptor, with subsequent activation of the GTP-binding protein and its effector, adenylyl cyclase. The resulting increase in intracellul ar 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 fo r mutational activation have been defined. In addition, mutations at s pecific loci of the a-subunit of G-protein in human thyroid tumors hav e been described. We examined 92 benign and malignant neoplastic thyro id tissues for possible mutations of the intracytoplasmic domains of t he TSH-R known to be involved in signal transduction and for mutations within the hot spots of G(s)alpha. Screening was carried out by singl e strand conformation polymorphism (TSH-R) or denaturing gradient gel electrophoresis (G(s)alpha) of polymerase chain reaction-amplified tum or DNA. No mutations were observed in the cytoplasmic domains of the T SH-R, except for a neutral base substitution in codon 460 (GCG [Ala]-- >CA [Ala]) in 3 tumors, which was also present in constitutional DNA f rom the affected individuals. A heterozygous mutation of codon 201 of G(s)alpha (GGT [Arg]-CAT [His]) was observed in a nodule from an adeno matous goiter. In addition, a codon 227 mutation (CAG [Glu]-CAT [His]) was identified in a follicular adenoma. We conclude that mutational a ctivation of the intracytoplasmatic domains of the TSH-R is not a sign ificant mechanism of thyroid tumorigenesis, whereas putative activatin g mutations within exons 8 and 9 of G(s)alpha occur infrequently in so me benign follicular tumors.