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BRAF Mutations in Papillary Thyroid Carcinomas Inhibit Genes Involved in Iodine Metabolism

Departments of Clinical Sciences (C.D., R.M., A.S., A.V., E.T., S.F.) and Experimental Medicine (E.F., A.G.), University of Rome "La Sapienza," 00161 Rome, Italy; Department of Internal Medicine (E.P., S.M., F.B.), Endocrine Surgery Unit, Regional Referral Centre (N.A.), and Institute of Pathology (A.C.), University of Perugia, 06126 Perugia, Italy; Unit of Endocrinology (R.B.), Tinchi-Pisticci Hospital, 75020 Matera, Italy; Department of Pharmacobiological Sciences (D.R.), University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy; and Neuromed Institute (A.G.), 86077 Pozzilli, Italy

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., 2a Clinica Medica, Dipartimento di Scienze Cliniche Università degli Studi di Roma "La Sapienza," V.le del Policlinico, 155-00161 Rome, Italy. E-mail: sebastiano.filetti{at}uniroma1.it.

Context: BRAF mutations are common in papillary thyroid carcinomas (PTCs). By affecting the expression of genes critically related to the development and differentiation of thyroid cancer, they may influence the prognosis of these tumors.

Objective: Our objective was to characterize the expression of thyroid-specific genes associated with BRAF mutation in PTCs.

Design/Setting and Patients: We examined the expression of key markers of thyrocyte differentiation in 56 PTCs with BRAF mutations (BRAF-mut) and 37 with wild-type BRAF (BRAF-wt). Eight samples of normal thyroid tissue were analyzed as controls. Quantitative PCR was used to measure mRNA levels for the sodium/iodide symporter (NIS), apical iodide transporter (AIT-B), thyroglobulin (Tg), thyroperoxidase (TPO), TSH receptor (TSH-R), the transcription factor PAX8, and glucose transporter type 1 (Glut1). NIS protein expression and localization was also analyzed by immunohistochemistry.

Results: mRNA levels for all thyroid-specific genes were reduced in all PTCs vs. normal thyroid tissues. NIS, AIT-B, Tg, and TPO expression was significantly lower in BRAF-mut tumors than in the BRAF-wt group. Glut-1 transcript levels were increased in all PTCs, and additional increases were noted in BRAF-mut tumors. In both tumor subsets, the NIS protein that was expressed was abnormally retained in the cytoplasm.

Conclusion: BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. This effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mut PTCs.

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