title: RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series.
abstract: BACKGROUND
  Highly discrepant data about the different distribution of RET germline single nucleotide polymorphisms (SNPs) among patients with sporadic medullary thyroid cancer (sMTC) and controls are available.
  
  
  METHODS
  In the present case-control study, a wide panel of seven RET SNPs has been tested in the largest sMTC series and in a matched control group.
  
  
  RESULTS
  None of the investigated polymorphisms show a significantly different distribution in patients with sMTC when compared to controls. Twenty haplotypes and 57 genotypes were generated, and their association with the disease and with the clinical features were statistically evaluated. Interestingly, 14 genotypes were found to be unique to sMTC patients and 25 to controls. Two haplotypes and three genotypes, all including the intronic variants IVS1-126 and IVS14-24, were significantly associated with sMTC patients and with a higher tumour aggression. The functional activity of the only nonsynonymous RET variant (c.2071C > A, G691S) was tested for the first time. Interestingly, Western blot analyses showed that the fraction of Ret9-G691S protein located at the plasma membrane level was overrepresented when compared to Ret9-WT, suggesting facilitated targeting at the cell membrane for this variant. However, no transforming activity was shown in a focus formation assay on cells carrying the Ret9-G691S, against a possible oncogenic role of G691S variant.
  
  
  CONCLUSIONS
  RET genotypes including two intronic RET variants were associated with the risk of developing sMTC and to more aggressive behaviour. Further studies are warranted to elucidate whether these RET genotypes are in linkage disequilibrium with another susceptibility gene or whether these variants could play a role in the genesis of sMTC per se.
authors.affiliation: Department of Medical Sciences, University of Milan, Milan, Italy. l.fugazzola@policlinico.mi.it
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
authors.forename: Marina
authors.initials: M
authors.lastname: Muzza
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
authors.forename: Daniela
authors.initials: D
authors.lastname: Cordella
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.forename: Luisella
authors.initials: L
authors.lastname: Alberti
authors.forename: Valentina
authors.initials: V
authors.lastname: Cirello
authors.forename: Davide
authors.initials: D
authors.lastname: Dazzi
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Girelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
mesh_terms: D000818:Animals; D018276:Carcinoma, Medullary / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007558:Italy; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human