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;pentagastrinstimulated,50100pg/ml)incomparisonwith 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 (IVS13158; NCBI rs2472737 IVS14–24) SNPs. Results: In FMTC patients, the F791Y mutation was found to be associated (P0.001) 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. (J Clin Endocrinol Metab 90: 6232–6236, 2005)