Polymorphisms in Exon 13 and intron 14 of the RET protooncogene:: Genetic modifiers of medullary thyroid carcinoma?

Context: Single-nucleotide polymorphisms (SNPs) of the RET protooncogene (RET) could modify disease susceptibility and clinical phenotype in patients with sporadic or familial medullary thyroid carcinoma (FMTC). Objective/ Design of the Study: Because frequencies of RET SNPs have not yet been evaluated in patients with elevated serum concentrations of calcitonin (hCt), a biochemical marker for medullary thyroid carcinoma (MTC), we studied RET SNPs in patients with FMTC (n = 22), patients with sporadic MTC (n = 45), and 71 subjects presenting with moderately elevated hCt concentrations (basal, > 10 pg/ ml; pentagastrin stimulated, > 50 < 100 pg/ml) in comparison with an age- and gender- matched control group (n = 79) with basal hCt concentrations in the normal range (< 5 pg/ ml). Methods: After DNA extraction from citrated whole blood, RET exons 10, 11, 13, 14, 15, and 16 and exon/ intron boundaries were analyzed by PCR-based cycle sequencing for RET germ line mutations, exonic (G691S, L769L, S836S, S904S) and intronic (IVS13 + 158; NCBI rs2472737 = IVS14 - 24) SNPs. Results: In FMTC patients, the F791Y mutation was found to be associated (P = 0.001) with the L769L SNP. The exonic SNPs (G691S, L769L, S836S, and S904S) were not different among the four groups. The intron 14 SNP (IVS14 - 24), however, was more frequent in individuals with elevated hCt serum concentrations (P = 0.016) and patients with sporadic MTC (P < 0.001) when compared with the control group. Conclusions: These data suggest that the exon 13 (L769L) and the intron 14 (IVS14 - 24) SNPs could act as genetic modifiers in the development of some forms of hereditary and sporadic MTC, respectively.