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In Vivo and in Vitro Characterization of a Novel Germline RET Mutation Associated with Low-Penetrant Nonaggressive Familial Medullary Thyroid Carcinoma

Unit of Endocrinology and Division of Anatomic Pathology (L.D., M.B.), Instituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo, 71013 Foggia, Italy; Dipartimento di Biologia e Patologia Cellulare e Molecolare (F.C., S.A., M.S), University Federico II c/o Istituto di Endocrinologia ed Oncologia Sperimentale Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; Dipartimento di Scienze Cliniche e Dipartimento di Medicina Sperimentale e Patologia (E.F., A.V., S.F.), Università di Roma La Sapienza, Viale del Policlinico 155-00161 Rome, Italy; and Dipartimento di Medicina Sperimentale e Clinica Gaetano Salvatore and Dipartimento di Scienze Farmacobiologiche (F.A., D.S., D.R.), University of Catanzaro Magna Graecia, 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Dipartimento di Scienze Cliniche Università di Roma La Sapienza, Viale del Policlinico 155-00100 Rome, Italy. E-mail: sebastiano.filetti{at}uniroma1.it.

Context: RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members.

Objective: The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation.

Design/Setting: RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing.

Patients: Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren.

Main Outcome Measures: DNA extracted from the blood and the proband’s tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated.

Results: A novel heterozygous germline RET mutation at codon 777 (AACAGC, NS) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC or C cell hyperplasia. The proband’s MTC was characterized by late onset and limited aggressiveness, with no evidence of regional lymph node or distant metastases 10 yr after total thyroidectomy. This phenotype is consistent with the RET/N777S mutant’s low-grade transforming potential and limited activation of RET tyrosine kinase.

Conclusion: Our findings indicate that the newly identified RET/N777S mutation is a low-penetrant cause of MTC disease. This phenotype might be less aggressive than that associated with MEN2A of familial MTC, although close clinical follow-up of carriers is essential.

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