title: Follicular carcinoma presenting as autonomous functioning thyroid nodule and containing an activating mutation of the TSH receptor (T620I) and a mutation of the Ki-RAS (G12C) genes.
abstract: Most autonomous functioning thyroid nodules (AFTN) are benign thyroid follicular neoplasms. There are rare reports of malignant hot nodules, in which activating mutations of the TSH receptor (TSHR) were found. We report a case of follicular carcinoma presenting as an AFTN causing subclinical hyperthyroidism in a 64-year-old woman who had a 6-cm hot nodule in the left thyroid lobe. Genomic DNA was extracted from paraffin-embedded tissues from the tumor and extratumoral thyroid tissue. Sequence analyses revealed point mutations in two different genes: the normal ACC sequence at codon 620 of the TSHR gene was replaced by ATC, changing the threonine by isoleucine (T620I); and the wild-type GGT at codon 12 of Ki-RAS mutated to TGT, replacing glycine by cysteine (G12C). In transfection experiments the T620I mutant showed constitutive activity in terms of cyclic adenosine monophosphate (cAMP) production when permanently transfected in 3T3 cells. Here, we describe for the first time an activating mutation in 3codon 620 of the TSHR. In addition, the cancerous AFTN also contained a G12C Ki-RAS mutation. We hypothesize that the combination of these two mutations might have played an important role in both the hyperfunction of the tumor and the carcinogenetic process.
authors.affiliation: Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina. hniepom@elsitio.net
authors.forename: Hugo
authors.initials: H
authors.lastname: Niepomniszcze
authors.forename: Horacio
authors.initials: H
authors.lastname: Suárez
authors.forename: Fabián
authors.initials: F
authors.lastname: Pitoia
authors.forename: Analía
authors.initials: A
authors.lastname: Pignatta
authors.forename: Karina
authors.initials: K
authors.lastname: Danilowicz
authors.forename: Marcos
authors.initials: M
authors.lastname: Manavela
authors.forename: Boris
authors.initials: B
authors.lastname: Elsner
authors.forename: Oscar D
authors.initials: OD
authors.lastname: Bruno
mesh_terms: D016475:3T3 Cells; D018263:Adenocarcinoma, Follicular / Q000175:diagnosis* / Q000235:genetics*; D000818:Animals; D003062:Codon; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013961:Thyroid Gland / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D003062:Codon; D011989:Receptors, Thyrotropin; D004247:DNA; D000242:Cyclic AMP