CLONAL ORIGIN OF TOXIC THYROID-NODULES WITH CONSTITUTIVELY ACTIVATINGTHYROTROPIN RECEPTOR MUTATIONS

Constitutively activating TSH receptor mutations have recently been de tected in toxic nodules. In vitro studies suggest that mutated recepto r signaling constitutively elevates cAMP, which causes hyperfunction a nd proliferation of thyrocytes. Therefore, toxic nodules with constitu tively activating somatic TSH receptor mutations should result from cl onal expansion of a single mutated cell. To test this hypothesis, we s tudied the clonal origin of 27 toxic nodules. In 13 of 27 nodules, a s omatic mutation in the TSH receptor was identified. A PCR-based clonal ity assay that analyzes X-chromosome inactivation was used. The assay amplifies a polymorphism located in the androgen receptor gene. Of 27 toxic nodules studied, 23 (85%) were informative for the polymorphism. In the group that contains a somatic mutation in the TSH receptor, 10 of 11 cases showed nonrandom X inactivation, indicating clonal expans ion. In only one toxic nodule with a TSH receptor mutation was random X inactivation detected. In the group without detectable mutations in exons 9 and 10 of the TSH receptor and exons 7-10 of the G(s) alpha pr otein, only 6 of 12 toxic nodules show nonrandom X-chromosome inactiva tion. Therefore, the majority of toxic nodules with constitutively act ivating TSH receptor mutations are of clonal origin. This finding supp orts the hypothesis that toxic nodules arise from aberrant growth of a single cell. It is widely accepted that somatic mutations might initi ate monoclonal growth. The TSH receptor mutations in these toxic nodul es together with G(s) alpha mutations in others are the most likely ca ndidates for the initiation of this thyroid tumor. The clonal origin o f toxic nodules in the group without detected mutations in the TSH rec eptor or the G(s) alpha protein suggests somatic mutations in genes th at are unknown to date.