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Absence of Activating Mutations of the Genes Encoding the -Subunits of G₁₁ and G_q in Thyroid Neoplasia¹

Division of Endocrinology and Metabolism (M.D.R., W.F.S., M.A.L.) and Division of Endocrine and Oncologic Surgery (M.S., D.S., M.A.Z.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Michael A. Levine, M.D., Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Room 863, Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205. E-mail: mlevine{at}welchlink.welch.jhu.edu

Activating mutations of the TSH receptor and -subunit of G_s (G_s) that increase adenylyl cyclase activity have been identified in a subset of hyperfunctioning benign thyroid follicular adenomas and, less commonly, in hypofunctioning adenomas and carcinomas. In addition, some thyroid tumors exhibit inappropriate activation of phospholipase C (PLC), a signaling pathway that has been implicated in the growth and dedifferentiation of thyroid cells. We therefore hypothesized that some thyroid tumors might be caused by somatic mutations in the genes encoding the -chain of G_q or G₁₁ that result in constitutive activation of the PLC pathway. We amplified regions of the _q and ₁₁ genes that encode amino acids, Q209 and R183, and we screened the DNA for mutations by sequence analysis and denaturing gradient gel electrophoresis. No mutations were identified after analysis of DNA from 38 thyroid tumors and 2 poorly differentiated thyroid carcinoma cell lines, including: 13 follicular adenomas, 10 follicular carcinomas, 5 papillary carcinomas, and 10 hyperplastic nodules from multinodular goiters. We conclude that activating mutations of _q and ₁₁ are absent or rare in hypofunctioning thyroid neoplasms and that other mechanisms must explain the elevated PLC activity reported in thyroid carcinoma.

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