title: A new germline point mutation in Ret exon 8 (cys515ser) in a family with medullary thyroid carcinoma.
abstract: BACKGROUND
  A novel Cys-Ser Ret germline point mutation in a 58-year-old woman with bilateral medullary thyroid carcinoma (MTC) prompted us to perform genetic analysis of the family and evaluate the biological consequences of such a mutation.
  
  
  METHODS
  Ret analysis by direct sequencing was performed in five family members. The biological activity and biochemical properties of the Ret- Cys515Ser mutant were analyzed in NIH-3T3 cells.
  
  
  RESULTS
  The proband's son, age 35, had the Ret- Cys515Ser mutation and the L769 CTT/CTG exon 13 polymorphic variant, which was also found in his father. Clinical evaluation of the son also revealed bilateral multifocal microscopic MTC and papillary thyroid carcinoma (PTC). In vitro and in vivo analysis indicated ligand-independent activation of the Ret-Cys515Ser mutant due to aberrant disulfide homodimerization, increased mitogenic activity, and ability to induce anchorage-independent growth in NIH-3T3 cells in comparison to wild-type Ret, suggesting a possible role of Cys515Ser in tumor development.
  
  
  CONCLUSIONS
  The Cys515Ser mutation adds to cysteine substitution groups that have been described in association with MTC. Our data also highlight the importance of performing a complete genetic analysis in patients who present with MTC.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Department of Molecular Pathology and Innovative Therapies, Polytechnic University of the Marche Region, Ancona, Italy. fazioli@univpm.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Fazioli
authors.forename: Gina
authors.initials: G
authors.lastname: Piccinini
authors.forename: Gloria
authors.initials: G
authors.lastname: Appolloni
authors.forename: Roberta
authors.initials: R
authors.lastname: Bacchiocchi
authors.forename: Gioia
authors.initials: G
authors.lastname: Palmonella
authors.forename: Rina
authors.initials: R
authors.lastname: Recchioni
authors.forename: Elisa
authors.initials: E
authors.lastname: Pierpaoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Silvetti
authors.forename: Marina
authors.initials: M
authors.lastname: Scarpelli
authors.forename: Matteo
authors.initials: M
authors.lastname: Bruglia
authors.forename: Rosa Marina
authors.initials: RM
authors.lastname: Melillo
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.forename: Augusto
authors.initials: A
authors.lastname: Taccaliti
mesh_terms: D018276:Carcinoma, Medullary / Q000235:genetics* / Q000601:surgery; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000601:surgery; D013965:Thyroidectomy
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human