ACTIVATING MUTATIONS OF THE TSH RECEPTOR IN DIFFERENTIATED THYROID CARCINOMAS

A series of 14 thyroid carcinomas, characterized for their basal adeny l cyclase activity (ACA), was examined for the presence of activating point mutations in the TSH receptor (TSHR) gene, Sequencing of the car boxyl-part of this gene revealed the presence of a somatic and heteroz ygotic point mutation in codon 623 in three out of six tumors showing a constitutively enhanced ACA and a poor response to TSH stimulation. The mutation determines the substitution of a serine for an alanine in the third intracellular loop of the receptor, in a region critical fo r signal transduction. One tumor bearing a TSHR mutation presented als o a N-ras point mutation. Both mutations were detected also in a lung metastasis of this tumor, Our data represent the first report of alter ations in the TSHR gene in thyroid malign neoplasia, TSHR mutations ma y indeed participate, as web as the G alpha(s) protein (gsp oncogene), in the oncogenesis of some differentiated thyroid carcinomas presenti ng increased basal levels of cAMP and a poor response to TSH.