title: Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma.
abstract: 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.
authors.affiliation: Unit of Endocrinology and Division of Anatomic Pathology, Istituto di Ricovero e Cura a Carattere Scientifico-Csa Sollievo della Sofferenza Hospital, Foggia, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Aloiso
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
authors.forename: Michele
authors.initials: M
authors.lastname: Bisceglia
authors.forename: Suresh
authors.initials: S
authors.lastname: Anaganti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.forename: Franco
authors.initials: F
authors.lastname: Arturi
authors.forename: Daniela
authors.initials: D
authors.lastname: Scarpelli
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
mesh_terms: 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
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human