CLINICAL STUDY Decreased expression of thyrotropin receptor gene suggests a high-risk subgroup for oncocytic adenoma Delphine Mirebeau-Prunier 1 , Serge Guye ´tant 2 , Patrice Rodien 1,4 , Brigitte Franc 3 , Olivier Baris 1 , Vincent Rohmer 1,4 , Pascal Reynier 1 , Yves Tourmen 1 , Yves Malthie `ry 1 and Fre ´de ´rique Savagner 1 1 INSERM E 00-18 Laboratoire de Biochimie et Biologie mole ´culaire, CHU, Angers F-49033, France, 3 Laboratoire d’Anatomie Pathologique, Ho ˆpital Ambroise Pare ´, AP-HP, Boulogne F-92104, France and 2 Laboratoire d’Anatomie Pathologique and 4 Service d’Endocrinologie (P R), Nutrition et Me ´decine interne, CHU, Angers F-49033, France (Correspondence should be addressed to D Mirebeau-Prunier, INSERM E 00-18 Laboratoire de Biochimie et Biologie mole ´culaire, CHU, 4 rue Larrey F-49033 Angers Cedex 01, France; Email: DeMirebeau-Prunier@chu-angers.fr) Abstract Objective: The malignancy of thyroid oncocytic tumours, or oncocytomas, is higher than that of follicular tumours. The aim of this study was to investigate the role of thyroid-specific genes in oncocytic tumours and papillary carcinomas. Design and methods: We compared 29 oncocytic tumours with 12 papillary carcinomas. Real-time quantitative PCR was used to measure the expression of thyroid-specific differentiation markers (thyr- otrophin-stimulation hormone receptor (TSHR), thyroglobulin (TG) and Na þ /I 2 symporter (NIS)), transcription factors (thyroid transcription factor-1 (TTF-1) and paired box gene-8 (PAX8)) and nuclear receptors (peroxisome proliferator-activated receptor (PPARg1) and thyroid hormone recep- tor (TRb1)) involved in thyroid carcinogenesis. Results: TSHR, TTF-1 and TRb1 levels were significantly lower in oncocytic tumours than in papillary carcinomas, as a result of specific biological changes in oncocytic tumours. However, PAX8 and PPARg1 did not seem to be involved in the process. Applying the criterion of the underexpression of the thyroid-specific differentiation markers, TSHR, TG and NIS, we classified the oncocytic tumours and papillary carcinomas into three groups. In the first, all three markers were underexpressed; in the second, TSHR was normal while TG and NIS were underexpressed; and in the third, only NIS was underexpressed. The expression patterns revealed that 13 of the 24 oncocytic adenomas underexpres- sing TSHR in our study, as did four of the five oncocytic carcinomas. Conclusion: Cases of oncocytic adenoma associated with four levels of TSHR could be putative onco- cytic carcinomas and should therefore receive adequate follow-up. European Journal of Endocrinology 150 269–276 Introduction Oncocytes are epithelial cells characterised by an abundant cytoplasm that takes on a finely granular eosinophilic staining, indicating the presence of large numbers of mitochondria (1). These cells, frequently found in organs with high metabolic activity, are associated with inflammation, degenerative processes and cellular ageing. Oncocytes undergo neoplastic transformation but oncocytic tumours or oncocytomas are rare, except in the thyroid and the kidney (2). Onco- cytic adenomas and carcinomas or Hu ¨ rthle cell thyroid tumours represent a distinct subgroup of follicular tumours. In these tumours, capsular and vascular invasions occur more frequently than in non-oncocytic follicular tumours. Moreover, the mortality rate is higher in oncocytic carcinomas than in papillary or follicular carcinomas (3). The relatively high rate of malignancy and aggressiveness of thyroid oncocytic tumours contrasts with the benign nature of most oncocytic tumours in other organs (4, 5). In the normal thyroid, the growth and differentiation of follicular cells are mainly regulated by the thyrotro- phin-stimulating hormone (TSH) through its receptor (TSHR), a member of the family of G-protein-coupled receptors. Stimulation of TSHR activates two major signal-transduction pathways: the adenylcyclase path- way through the guanine nucleotide-binding protein alpha subunit (GNAS) and the phospholipase C pathway through the Gq protein alpha subunit (6). Somatic mutations of TSHR and GNAS genes have been pre- viously reported in toxic adenomas as well as in thyroid follicular carcinomas (7–9). Differentiated thyroid cells express the TSHR, thyroglobulin (TG), thyroperoxidase (TPO) and the Na þ /I 2 symporter (NIS) genes. The expression of these genes is controlled by specific transcription factors: thyroid transcription factors 1 and 2 (TTF-1 and TTF-2), and paired box gene-8 European Journal of Endocrinology (2004) 150 269–276 ISSN 0804-4643 q 2004 Society of the European Journal of Endocrinology Online version via http://www.eje.org