ORIGINAL ARTICLE RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC) C. Romei* , †, B. Cosci* , †, G. Renzini* , †, V. Bottici* , †, E. Molinaro* , †, L. Agate* , †, P. Passannanti* , †, D. Viola* , †, A. Biagini* , †, F. Basolo‡, C. Ugolini‡, G. Materazzi‡, A. Pinchera* , † , §, P. Vitti* , † and R. Elisei* , † *Department of Endocrinology and Metabolism, †WHO Collaborating Center for the Diagnosis and Treatment of Thyroid Cancer and Other Thyroid Diseases, ‡Department of Surgery and §AMBISEN Center, High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, Pisa, Italy Summary Objective This study was aimed to demonstrate the clinical ben- efits of rearranged during transfection (RET) genetic screening in patients with apparently sporadic medullary thyroid cancer (MTC) not only to identify the hereditary nature of the disease in the index case but also to discover family members harbouring the same germline mutations (i.e. gene carriers) who are unaware of their condition. Context RET genetic screening allowed the identification of germline RET mutations in apparently sporadic MTC resulting in their re-classification as hereditary forms. Patients and measurements RET genetic screening was per- formed in 729 apparently sporadic MTC patients by direct sequencing RET exons 5, 8, 10, 11 and 13–16. Clinical and bio- chemical evaluation of gene carriers was also performed. Results We discovered an unsuspected germline RET mutation in 47 of 729 (6Æ5%) apparently sporadic MTC who were re-classi- fied as hereditary. We found 60 of 146 (41Æ1%) gene carriers, 35 of whom had biochemical or clinical evidence of MTC. Thirty gene carriers underwent total thyroidectomy and 27 of 30 (90%) were persistently cured after a mean follow-up of 6Æ0 years. As a further result of RET genetic screening, we observed a significantly higher prevalence of familial medullary thyroid cancer (FMTC) in our ser- ies with respect to the largest series of the International RET Con- sortium (P =0Æ0002). Conclusions RET genetic screening of patients with apparently sporadic MTC represents a major tool for the preclinical diagnosis and early treatment of unsuspected affected family members and allows the identification of a relevant percentage of hidden FMTC. (Received 20 August 2010; returned for revision 3 September 2010; finally revised 20 September 2010; accepted 6 October 2010) Introduction Medullary thyroid carcinoma (MTC) is a rare tumour arising from parafollicular thyroid C cells 1,2 and can occur sporadically (70– 80% of patients) or as part of the multiple endocrine neoplasia (MEN) type 2 syndromes (20–30% of patients). In these patients, other endocrine organs (i.e. parathyroid and adrenal glands) may be involved, and three different syndromes, MEN 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC), can be distin- guished. 3–5 Clinical classification of MEN 2 has been established based on the spectrum of clinical manifestations in the index case and in other affected members of the family. When a phaeochrom- ocytoma (PHAEO) and/or a primary hyperparathyroidism (hyper- PTH) is present in a patient with MTC or in some relatives, MEN 2A syndrome can be diagnosed. 6 The clinical feature of a marfanoid habitus with mucosal neurinomas with or without associated PHAEO in a subject with MTC is suggestive of MEN 2B syn- drome. 7,8 Finally, when several members of the same family have a history of MTC with no evidence of involvement of any other endocrine gland, a diagnosis of an FMTC syndrome can be advo- cated. 6,9 According to the literature, the clinical prevalence of the three hereditary syndromes is about 60% for MEN 2A, 10% for MEN 2B and 30% for FMTC. Conversely, the sporadic form of MTC is defined by the absence of a familial history of MTC and of the other MEN 2-related tumours. In 1993, RET germline mutations were recognized as the causa- tive molecular alterations in MEN 2 syndromes. 10–12 A very fruitful literature has been produced during these years showing a strong genotype–phenotype correlation in the MEN 2 syndromes with Cys634 mutations mainly relating to the MEN 2A and the Met918Thr mutation exclusively present in MEN 2B. 6,13,14 As Correspondence: R. Elisei, Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. Tel.: 0039 050 995120; Fax: 0039 050 578772; E-mail: relisei@endoc.med.unipi.it Dr. C. Romei and Dr. B. Cosci equally contributed to this paper. Clinical Endocrinology (2011) 74, 241–247 doi: 10.1111/j.1365-2265.2010.03900.x Ó 2011 Blackwell Publishing Ltd 241