THYROTROPIN RECEPTOR GENE ALTERATIONS IN THYROID HYPERFUNCTIONING ADENOMAS

Forty-four thyroid autonomously hyperfunctioning adenomas were analyze d to assess the frequency of mutations occurring in the TSH receptor ( TSHR). PCR-amplified fragments encompassing the entire exon 10 of the TSHR gene were obtained from the genomic DNA extracted from the tumors and their adjacent normal tissues and were examined by direct nucleot ide sequencing. Point mutations were found in 9 of the 44 adenomas exa mined (20%). One mutation occurred in codon 619 (Asp to Gly), four in codon 623 (three were Ala to Ser, one Ala to Val substitution), two in codon 632 (both Thr to Ile), and two in codon 633 (Asp to Tyr or His) . All the alterations were located in a part of the gene coding for an area including the third intracellular loop and the sixth transmembra ne domain of the TSH receptor. All mutations were somatic and heterozy gotic, and none was simultaneous with alterations of ras or gsp oncoge nes. Thus, our data show that in our series of 44 hyperfunctioning thy roid adenomas, a somatic mutation of the TSHR, responsible for the con stitutive activation of the cAMP pathway, occurs in 20% of the tumors.