Medullary carcinoma of the thyroid (MTC) may occur either as sporadic (75%) or hereditary (25%) disease. Hereditary MTC can occur either alone – familial MTC (FMTC) – or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes (MEN2A and MEN2B) or others. Germline mutations in the Ret proto-oncogene cause MEN2 and recent studies suggest a relationship between specific mutations and different phenotypes in MEN2 syndromes. The purpose of this study was to identify Ret mutations and analyze the relationship between genotype-phenotype. A total of 48 individuals with MTC were enrolled in this study, 7 with apparent sporadic carcinoma and 41 from 14 separate hereditary MTC families. DNA was extracted from leukocytes and exons 10, 11, 13, 14 and 16 were amplified by PCR. The mutation was determined by SSCP, enzymatic restriction analysis and/or sequencing. The phenotypes of hereditary MTC were as follows: 7 MEN2A, 2 MEN2A+CLA, 2 MEN2B, 2 FMTC and 1 other forms. We identified mutations at codon 634 (TGC->CGC or TGC->TAC) in 6 of the 7 families with MEN2A. One kindred had the mutation in codon 618 (TGC->CGC). The 2 kindred with MEN2A+CLA presented the mutation in codon 634 (TGC->CGC). In both cases of FMTC the mutation was also found in the codon 634 (TGC->CGC). A mutation at codon 918 (ATG->AGC) was identified in the 2 subjects with MEN2B, whereas in the other hereditary forms of the MTC, we identified a mutation at codon 634 (TGC->TAC). The genetic screening was able to identify mutations in all individuals with a hereditary pattern, in 8 assymptomatic carriers and in 2 subjects with apparently sporadic tumors. Our results confirm the literature in that genetic testing is a fundamental tool for the management of hereditary MTC.
Medullary thyroid carcinoma; Proto-oncogene Ret; MEN 2A; MEN 2B; FMTC
