A Val 677 activating mutation of the thyrotropin receptor in a Hürthle cell thyroid carcinoma associated with thyrotoxicosis.

Thyroid nodules presenting as hot at 131I-scintigraphy are usually benign follicular adenomas. We report a 42-year-old female patient with an autonomously functioning Hürthle cell thyroid carcinoma causing thyrotoxicosis. Genetic analysis of her thyroid tumoral DNA revealed a heterozygotic activating mutation of the thyrotropin receptor (TSHR) gene that was located downstream to all of the other genetic alterations currently identified, and is due to a base substitution at codon 677 (normal cytosine replaced by guanine, CTG for GTG causing leucine substitution by valine in the seventh transmembrane domain of the receptor). This mutation was detected in the tumor, but not in the leucocytes from the same patient. The Val 677-TSHR mutant showed constitutive activity, in terms of cyclic adenosine monophosphate (cAMP) production, when permanently transfected in Chinese hamster ovary (CHO) cells. Gsp and ras oncogenes and the p53 tumor suppressor gene were not present in the Hürthle cell cancer. The TSHR mutation in this Hürthle cell carcinoma may be responsible for maintaining differentiated thyroid function and hyperthyroidism.