title: Analysis of RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma.
abstract: BACKGROUND
  Little is known about the etiology of sporadic medullary thyroid carcinoma (sMTC). While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, the molecular mechanisms leading to the sporadic forms remain obscure. Our group had evidence about the existence of a low-penetrance susceptibility locus for sMTC in linkage disequilibrium with RET variants S836S/IVS1-126G>T, and probably in 5' with respect to both variants. In this study we sought to identify such locus. On the other hand, because an overrepresentation of G691S/S904S variants in patients with sMTC had been previously reported, we sought to determine if such association was present in our series.
  
  
  METHODS
  We performed a case-control study analysing a wide spectrum of RET variants in the 5' region of the gene, as well as the variants G691S/S904S. Haplotype distribution were also analyzed. A total of 58 patients with sMTC were included in the study. In addition, 100 unselected, unrelated race-, age-, and gender-matched normal controls were also evaluated.
  
  
  RESULTS
  Although the overrepresentation of IVS1-126G>T remains present in our current sMTC series, thus supporting our previous hypothesis, no differences were obtained among cases and controls in the distribution of the variants tested upstream this position. On the other hand, the frequency and distribution of G691S/S904S variants were similar in both groups of study, leading to exclude their role in sMTC in our series.
  
  
  CONCLUSIONS
  These findings would suggest that the major genetic events contributing to the appearance of sMTC may reside in several different RET loci. In this way, we could hypothesize about the existence of at least two sMTC loci, linked to S836S-IVS1-126G>T, or to G691S-S904S, respectively.
authors.affiliation: Unidad Clínica de Genética y Reproducción, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Fernández
authors.forename: Ana
authors.initials: A
authors.lastname: Peciña
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.forename: Elena
authors.initials: E
authors.lastname: Navarro
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
mesh_terms: D018276:Carcinoma, Medullary / Q000235:genetics*; D031541:Fluorescence Resonance Energy Transfer; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret