title: Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness.
abstract: OBJECTIVE
  RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of medullary thyroid carcinoma (MTC). Here, we investigated the influence of multiple RET variants (G691S, L769L, S836S, and S904S) on the risk of MTC and tumor behavior.
  
  
  METHODS
  One hundred and seven MTC patients and 308 cancer-unaffected control individuals were included. SNPs were analyzed using Custom TaqMan Genotyping Assays. Haplotypes based on the combination of allelic variants were inferred using a Bayesian statistical method.
  
  
  RESULTS
  The minor allele frequencies in MTC patients were as follows: L769L: 28.0%, S836S: 8.9%, and G691S/S904S: 22.2%. The RET L769L and S836S SNPs were associated with increased risk of MTC (odds ratio (OR)=1.95, 95% CI: 1.2-3.1, P=0.005 and OR=2.29, 95% CI: 1.2-4.5, P=0.017 respectively). The adjusted OR for individuals harboring haplotypes with three or more polymorphic alleles was 3.79 (95% CI: 1.5-9.5; P=0.004), indicating an additive effect of these variants on the risk for MTC. Among MTC patients, no significant associations were observed between RET variants and age of diagnosis or tumor size but serum calcitonin levels increased according to the number of risk alleles (P=0.003). Remarkably, patients carrying haplotypes with three or four risk alleles had increased risk for lymph node and distant metastases at diagnosis (OR=5.84, 95% CI: 1.1-31.2, P=0.039). Further analysis using Kaplan-Meier model demonstrated that metastatic disease occurred earlier in individuals harboring multiple risk alleles.
  
  
  CONCLUSIONS
  Our results demonstrated an additive effect of RET polymorphic alleles on the estimated risk of developing aggressive MTC.
authors.affiliation: Thyroid Section, Endocrine Division, Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, 90035 -003 Porto Alegre, RS, Brazil.
authors.forename: Lucieli
authors.initials: L
authors.lastname: Ceolin
authors.forename: Débora Rodrigues
authors.initials: DR
authors.lastname: Siqueira
authors.forename: Carla Vaz
authors.initials: CV
authors.lastname: Ferreira
authors.forename: Mírian
authors.initials: M
authors.lastname: Romitti
authors.forename: Silvana Cavalcante
authors.initials: SC
authors.lastname: Maia
authors.forename: Leonardo
authors.initials: L
authors.lastname: Leiria
authors.forename: Daisy
authors.initials: D
authors.lastname: Crispim
authors.forename: Patrícia
authors.initials: P
authors.lastname: Ashton-Prolla
authors.forename: Patrícia Ashton
authors.initials: PA
authors.lastname: Prolla
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Maia
mesh_terms: D000328:Adult; D018278:Carcinoma, Neuroendocrine; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology*
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human