Thyrotropin receptor: a role for thyroid tumourigenesis?

Human thyroid tumours represent an example of the interplay of genetic and non genetic carcinogenesis. Recently, genetic abnormalities in the elements of the Thyrotropin receptor (TSH-R) dependent cAMP regulatory cascade have been found to be involved both in benign and malignant thyroid tumours. The presence of activating mutations has been demonstrated in the TSH-R gene as well as in the Gs alpha protein gene in thyroid toxic adenoma resulting in the constitutive activation of the cAMP pathway and it has been hypothesised that these genetic alterations may play a causative role in the disease. However, recent observations suggest more caution in accepting such a hypothesis. The presence of activating TSH-R mutations has also been demonstrated in differentiated thyroid carcinomas. At present, the percentage of such a modification is low, unless referred to selected series of tumours. Activating mutations of the TSH-R gene have been detected in a group of differentiated carcinomas with high basal adenylyl cyclase activity, and in a few cases of hyperfunctioning thyroid carcinoma. However, the role of the TSH-R-related cAMP pathway alterations in thyroid transformation remains to be elucidated. In this review, the role of TSH-R gene alterations in benign and malignant thyroid neoplasia is examined.