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This version published online on May 8, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2707
A more recent version of this article appeared on July 1, 2007
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Submitted on December 7, 2006
Accepted on April 27, 2007

BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism

C. Durante, E. Puxeddu, E. Ferretti, R. Morisi, S. Moretti, R. Bruno, F. Barbi, N. Avenia, A. Scipioni, A. Verrienti, E. Tosi, A. Cavaliere, A. Gulino, S. Filetti*, and D. Russo

Department of Clinical Sciences (C.D., R.M., A.S., A.V., E.T., S.F.) and Department of Experimental Medicine (E.F., A.G.), University of Rome "La Sapienza", 00161 Rome, Italy;Internal Medicine Department (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, Tinchi-Pisticci Hospital (R.B.), 75020 Matera, Italy; Department of Pharmacobiological Sciences, University of Catanzaro Magna Graecia (D.R.), 88100 Catanzaro, Italy

* To whom correspondence should be addressed. 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: To characterize the thyroid-specific genes expression 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 in BRAF-mut tumors were significantly lower than those in 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.
Key words: BRAF • NIS • TPO • radioiodine • thyroid carcinoma




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