title: Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer.
abstract: BACKGROUND
  Based on reports of higher frequencies among patients with sporadic medullary thyroid cancer (MTC) relative to external controls, the RET (REarranged during Transfection) variants G691S, L767L, S836S and S904S have been considered disease modifiers, suggesting greater lifetime risks of MTC. Other studies, employing different external controls, failed to confirm this association. Using a complementary approach, this study aimed at exploring differences in clinico-pathological characteristics among patients with sporadic MTC carrying no (wildtype), one (heterozygotes) or both (homozygotes) homologue RET variants in the germline, with wildtype cases acting as internal controls.
  
  
  METHODS
  Included in this investigation were 150 patients with complete genetic information on G691S, L769L, S836S and S904S RET alleles operated on for sporadic MTC at a tertiary referral centre.
  
  
  RESULTS
  Not one statistically significant dose-response relationship was identified between any RET variant (wildtype vs RET heterozygotes vs homologue RET homozygotes) and patient age at MTC diagnosis, gender, primary tumour size, extrathyroidal extension, numbers of involved and removed lymph nodes, or distant metastasis. L769L and S836S homozygotes, unlike G691S and S904S homozygotes, were either rare or absent, limiting the analyses to comparisons of heterozygosity versus wildtype. On time-to-event analysis, G691S, L769L, S836S or S904S carriers and noncarriers developed MTC at similar rates.
  
  
  CONCLUSIONS
  In carriers and noncarriers of the RET variants G691S, L767L, S836S and S904S, sporadic MTC appeared clinically and pathologically indistinguishable. This observation, along with the inconclusive evidence of previous association studies, calls for larger longitudinal association studies with age- and sex-matched external controls and additional functional studies of RET biology.
authors: Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. AndreasMachens@aol.com
authors: Andreas
authors: A
authors: Machens
authors: Karin
authors: K
authors: Frank-Raue
authors: Kerstin
authors: K
authors: Lorenz
authors: Susanne
authors: S
authors: Rondot
authors: Friedhelm
authors: F
authors: Raue
authors: Henning
authors: H
authors: Dralle
mesh_terms: D019943:Amino Acid Substitution; D000704:Analysis of Variance; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human