Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms

The molecular biology of follicular cell growth in thyroid nodules is still poorly understood. Because gain-of-function (activating) mutations of the thyroid-stimulating hormone receptor (TShR) and/or Gs alpha genes may confe r TSh-independent growth advantage to neoplastic thyroid cells, we searched for somatic mutations of these genes in a series of hyperfunctioning and n onfunctioning follicular thyroid adenomas specifically selected for their h omogeneous gross anatomy (single nodule in an otherwise normal thyroid glan d). TShR gene mutations were identified by direct sequencing of exons 9 and 10 of the TShR gene in genomic DNA obtained from surgical specimens. Codon s 201 and 227 of the Gs alpha gene were also analyzed. At histology, all hy perfunctioning nodules and 13 of 15 nonfunctioning nodules were diagnosed a s follicular adenomas. Two nonfunctioning thyroid nodules, although showing a prevalent microfollicular pattern of growth, had histological features i ndicating malignant transformation (a minimally invasive follicular carcino ma and a focal papillary carcinoma). Activating mutations of the TShR gene were found in 12 of 15 hyper-functioning follicular thyroid adenomas. In on e hyperfunctioning adenoma, which was negative for TShR mutations, a mutati on in codon 227 of the Gs alpha gene was identified. At variance with hyper functioning thyroid adenomas, no mutation of the TShR or Gs alpha genes was detected in nonfunctioning thyroid nodules. In conclusion, our findings cl early define a different molecular pathogenetic mechanism in hyperfunctioni ng and nonfunctioning follicular thyroid adenomas. Activation of the cAMP c ascade, which leads to proliferation but maintains differentiation of folli cular thyroid cells, typically occurs in hyperfunctioning thyroid adenomas. Oncogenes other than the TShR and Gs alpha genes are probably involved in nonfunctioning follicular adenomas.