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Background  The  RET  S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between  RET  S836S and 3'UTR variants has been reported in Hirschsprung's disease patients.    Objective  To evaluate the frequency of the  RET  3’UTR variants (rs76759170 and rs3026785) in MTC patients and to determine whether these variants are in LD with S836S polymorphism.    Methods  Our sample comprised 152 patients with sporadic MTC. The  RET  S836S and 3’UTR (rs76759170 and rs3026785) variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program.  RET  mRNA structure was assessed by Vienna Package.    Results  The mean age of MTC diagnosis was 48.5±15.5 years and 57.9% were women. The minor allele frequencies of  RET  polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3’UTR variants (|D’| = -1, r 2  = 1 and |D’| = -1, r 2  = 0,967). Patients harboring the S836S/3’UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P<0.001, respectively). Accordingly, RNA folding analyses demonstrated different RNA secondary structure predictions for WT( TCCGT ), S836S( T T CGT ) or 3’UTR(  GT C AC  ) haplotypes. The S836S/3’UTR haplotype presented a greater number of double helices sections and lower levels of minimal free energy when compared to the wild-type haplotype, suggesting that these variants provides the most thermodynamically stable mRNA structure, which may have functional consequences on the rate of mRNA degradation.    Conclusion  The  RET  S836S polymorphism is in LD with 3’UTR variants.  In silico  analysis indicate that the 3’UTR variants may affect the secondary structure of  RET mRNA , suggesting that these variants might play a role in posttranscriptional control of the  RET  transcripts.

Effect of 3′UTR RET Variants on RET mRNA Secondary Structure and Disease Presentation in Medullary Thyroid Carcinoma