Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma.
BACKGROUND
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.


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


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


METHODS
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 (AAC-->AGC, N-->S) (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.


CONCLUSIONS
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.
D'Aloiso
Leonardo
L
Unit of Endocrinology and Division of Anatomic Pathology, Istituto di Ricovero e Cura a Carattere Scientifico-Csa Sollievo della Sofferenza Hospital, Foggia, Italy.
Carlomagno
Francesca
F
Bisceglia
Michele
M
Anaganti
Suresh
S
Ferretti
Elisabetta
E
Verrienti
Antonella
A
Arturi
Franco
F
Scarpelli
Daniela
D
Russo
Diego
D
Santoro
Massimo
M
Filetti
Sebastiano
S
D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D010375:Pedigree; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012867:Skin / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D014162:Transfection
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human