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Silencing of the Tumor Suppressor Gene SLC5A8 Is Associated with BRAF Mutations in Classical Papillary Thyroid Carcinomas

Unité Mixte de Recherche 369, Institut National de la Santé et de la Recherche Médicale/Université Claude Bernard Lyon 1 (UCBL), and Institut Fédératif de Recherche 62 (V.P., C.F.-P., C.D., S.S.-R., F.B.-C., B.R.), Faculté de Médecine Lyon-RTH Laennec, 69372 Lyon Cedex 08, France; Unité Fonctionnelle de Biologie Cellulaire (V.P., C.F.-P., H.G., B.R.), Hôpital Edouard-Herriot, 69437 Lyon Cedex 03, France; FRE 2692 Centre National de la Recherche Scientifique/UCBL (R.D.), Faculté de Médecine Grange Blanche, 69373 Lyon Cedex 08, France; and Lyon Thyroid Tumor Bank Organization (N.B.-D., M.D., J.-L.P., C.B., J.O., C.F.-P., F.B.-C., B.R.), 69437 Lyon, France

Address all correspondence and requests for reprints to: Professor Bernard Rousset, Institut National de la Santé et de la Recherche Médicale Unit 369, Faculté de Médecine Lyon-RTH Laennec, Rue Guillaume Paradin, 69372 Lyon Cedex 08, France. E-mail: u369{at}sante.univ-lyon1.fr.

SLC5A8, proposed as a thyroid apical iodide transporter, was recently defined as a Na⁺-coupled transporter of short-chain fatty acid. To document the expression pattern of SLC5A8 in the thyroid, we analyzed the regulation of its expression in normal human thyrocytes in culture and in tissues with distinct functional activity. To determine whether SLC5A8 expression is altered in all thyroid carcinomas or only in particular subtypes, we investigated the level of its expression in a series of 50 hypofunctioning tumors. SLC5A8 expression was studied at the transcript level and compared with that of SLC26A4 or Pendrin and SLC5A5 or Na⁺/iodide symporter. SLC5A8 expression, unlike that of SLC5A5 and SLC26A4, was not regulated by TSH in normal human thyrocytes in culture and was not related to the functional state of thyroid tissue; toxic adenomas and adjacent resting tissues exhibited the same SLC5A8 transcript content. SLC5A8 expression was selectively down-regulated (40-fold) in papillary thyroid carcinomas of classical form (PTC-cf.). Methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of PTC-cf. and in about 20% of other papillary thyroid carcinomas. In a series of 52 PTC-cf., a low SLC5A8 expression was highly significantly associated with the presence of BRAF T1796A mutation. These data identify a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the T1796A point mutation of the BRAF gene in the PTC-cf. subtype of thyroid carcinomas.

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