CLINICAL IMPACT OF RET GENETIC SCREENING IN THE MANAGEMENT OF MEDULLARY THYROID CARCINOMA (MTC) PATIENTS: 20 YEARS OF EXPERIENCE

During the last 20 years, we performed RET genetic screening in 1556 subjects: 1007 arrived as affected by an apparently sporadic form of MTC and 95 were clearly affected by a hereditary form. The remaining 454 were relatives of RET positive MTC patients. An unsuspected germline RET mutation was found in 69/1007(6.7%) apparently sporadic MTC patients and were reclassified as hereditary: 60 FMTC and 8 MEN 2A syndromes were identified. The remaining 939 patients were RET negative thus their sporadic nature was confirmed. Ninety-five patients, 71 index cases and 24 relatives, arrived at our first clinical observation as affected by a hereditary MTC. A germline RET mutation was found in 69/71 index cases. The 71 families were classified in FMTC (n=33), MEN 2A (n=26), MEN 2B (n=12). A total of 140 MEN 2 families (94 FMTC, 34 MEN 2A, 12 MEN 2B) have been diagnosed. Following the identification of a germline RET mutations in the index cases, 454 relatives performed the RET screening and 137 were found to be gene carriers (GC). RET screening allowed us to identify 33 different mutations. The V804M (exon 14) is the most prevalent mutation (22.4%), but codon 634 (exon 11) is the most frequent (n = 34). MEN 2A syndromes are mainly associated to the C634R mutation while the MEN 2B to the M918T mutation. Among all mutations we found rare variants (R833C, A883T, M848T, M918V, E632K, S904F, T338I, V648I) whose biological significance has to be proven. On the basis of our experience, the clinical impact of the RET genetic screening can be summarized as follows: 1) identification of hereditary cases (7-8%) that would be clinically considered as sporadic; 2) identification of GC unaware of their condition thus allowing their early treatment; 3) identification of new RET mutations not necessarily pathogenetic for the disease.