A new germline point mutation in Ret exon 8 (cys515ser) in a family with medullary thyroid carcinoma.
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.
Fazioli
Francesca
F
Laboratory of Cellular and Molecular Biology, Department of Molecular Pathology and Innovative Therapies, Polytechnic University of the Marche Region, Ancona, Italy. fazioli@univpm.it
Piccinini
Gina
G
Appolloni
Gloria
G
Bacchiocchi
Roberta
R
Palmonella
Gioia
G
Recchioni
Rina
R
Pierpaoli
Elisa
E
Silvetti
Francesca
F
Scarpelli
Marina
M
Bruglia
Matteo
M
Melillo
Rosa Marina
RM
Santoro
Massimo
M
Boscaro
Marco
M
Taccaliti
Augusto
A
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
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human