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Submitted on June 7, 2005
Accepted on August 8, 2005
Department for Internal Medicine III, Division of Endocrinology and Metabolism, Core Unit of Medical Statistics and Informatics, Department of Surgery, Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
* To whom correspondence should be addressed. E-mail: sabina.baumgartner-parzer{at}meduniwien.ac.at.
Context: Single nucleotide polymorphisms (SNPs) of the RET proto-oncogene (RET) could modify disease susceptibility and clinical phenotype in patients with sporadic or familial medullary thyroid carcinoma (FMTC).
Objective/design of the study: Since frequencies of RET SNPs have not yet been evaluated in patients with elevated serum concentrations of calcitonin (hCt), a biochemical marker for MTC, we studied RET SNPs in i) patients with FMTC (n = 22), ii) patients with sporadic MTC (n = 45) and in iii) 71 subjects presenting with moderately elevated hCt concentrations (basal: >10 pg/ml; pentagastrin stimulated: >50 < 100 pg/ml) in comparison to 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 between the four groups. The intron 14 SNP (IVS14-24), however, was more frequent in individuals with elevated hCt serum concentrations (P = 0.016) and in patients with sporadic MTC (P < 0.001) when compared with the control group.
In conclusion, 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 of sporadic MTC, respectively.
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