Elisei R.1, Mariotti S.2, Fugazzola L.3, Taccaliti A.4, Pacini F.5, Opocher G.6, Castellano M.7, Degli Uberti E.C8, Ceccherini I.9, Cremonini N.10, Seregni E.11, Orlandi F.12, Ferolla P.13, Colao A.14, Puxeddu E.15, Romei Co1, Cosci B.1, Pinna G.2, Persani L.3, Boscaro M.4, Castagna M.G.5, Mian C6, Cappelli C.7, Zatelli M.C8, Pinchera A.1
1 Dept. of Endocrinolgy, University of Pisa, Pisa; 2Dept of Medical Sciences M. Aresu, University of Cagliari, Cagliari; 3Dept. of Medical Sciences, University of Milan, Milan; 4Dept. of Endocrinology, Polytechnic University of the Marche, Ancona; 5Dept of Internal Medicine, Endocrinology & Metabolism and Biochemist, University of Siena, Siena; 6Dept of Medical and Surgical Sciences, University of Padua, Padua; 7Dept of Medical and Surgical Sciences, Internal Medicine and Endocrinology Unit, University of Brescia, Brescia; 8Dept of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara; 9Molecular Gentics Lab, Gaslini Institute, Genoa; 10Dept of Endocrinology and Metabolic Diseases, Ospedale Maggiore, Bologna, Bologna; 11lstituto Nazionale dei Tumori, Milano; 12Dept of Clin ical and Biological Sciences, University of Turin, Orbassano; 13Dept of lnternal Medicine and Endocrine Sciences, University of Perugia, Perugia; 14Dept of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Naples; 15Department of Internal Medicine, University of Perugia, Perugia, Italy
Background: Multiple Endocrine Neoplasia is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not (FMTC) to other endocrine neoplasia due to germ line RET gene mutations. Over the years several different RET mutations have been described which prevalence is not known due to the small series size.
Patients: We collected data on RET mutations from 15 different Italian centres for a total of 199 families with hered ita ry MTC
Results: The most frequent RET aminoacid substitution was Val804Met (37/199, 18.6%) followed by Cys634Arg (29/199, 14.6%). However, the RET codon most frequently altered was Cys634 at exon 11 (n=66, 33.1 %). In particular the Cys634 mutations were distributed as follows: 29 Cys634Arg, 21 Cys634Tyr, 6 Cys634Phe, 4 Cys634Ser, 4 Cys634Gli and 2 Cys634Trp. The second most frequently altered codon was Val804 at exon 14 (n=40, 20%) with 37 Val804Met and 3 Va1804Leu. Fifteen RET mutations (7.5%) were found at codon 918 in exon 16. In 12 cases, all MEN 2B, they were represented by the classic Met918Thr. In 2 cases we found a Met918Vai and in 1 case a Met918Tyr associated with a FMTC We found 22 families with Ser891 Ala (11 %),14 families with Cys618Ser orGly or Arg orTyr (7%), 9 families with Glu768Asp (4.5%),8 families with Cys620Arg or Phe or Ser (4%) and 3 families with the Cys630Tyr or Arg (1.5%),4 families with Cys609Ser or Gly or Phe orTyr (2%). Mutation at codon 790 and 791 were rare (1.5% and 1% respectively) as well as Cys611 Gly, Cys515Ser, Ala883Thr, Arg694Gln, Lys666Asn+667ins-Ser, Lys666Met, Met848Thr, Ser904Phe, that were found in 7 different families (1/199, 0.5% each). Five families (5/199, 2.5%) were negative for germline RET mutations.
Conclusions: we observed a high prevalence ofVal804Met especially when comparing our series with those published by other European Study Groups. We feel that this difference can be due not only to the different populations and ethnic origin but also to the particular attention to analyse apparently sporadic MTC for RET germ line mutations.