RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series.
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.
Fugazzola
Laura
L
Department of Medical Sciences, University of Milan, Milan, Italy. l.fugazzola@policlinico.mi.it
Muzza
Marina
M
Mian
Caterina
C
Cordella
Daniela
D
Barollo
Susi
S
Alberti
Luisella
L
Cirello
Valentina
V
Dazzi
Davide
D
Girelli
Maria Elisa
ME
Opocher
Giuseppe
G
Beck-Peccoz
Paolo
P
Persani
Luca
L
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*
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human