MANAGEMENT OF HEREDITARY MEDULLARY THYROID CARCINOMA: CLINICAL IMPLICATIONS OF MOLECULAR DIAGNOSIS

Abstract

Hereditary MTC can occur either alone – familial MTC (FMTC) – or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or others. Three phenotypic subtypes have been reported. MEN 2A(1), MEN 2A(2) and MEN 2A(3). Germline mutations in the RET proto-oncogene cause MEN 2 and recent studies suggest a relationship between specific mutations and different phenotypes in MEN 2 syndromes. The purpose of this study was to identify RET proto-oncogene mutations and analyze a possible relationship between genotype-phenotype in Brazilian kindred with MTC. A total of 57 patients with histopathological and immunohistochemistry diagnosis of MTC were included. This sample was formed from index cases and affected members of 16 families
with hereditary MTC and 10 individuals with sporadic tumors. DNA was extracted from leukocytes of the affected individuals and relatives. Exons 10, 11, 13, 14, 15 and 16 were amplificated by PCR, using specific primers. The presence of mutation was determined by SSCP, enzymatic restriction analysis and/or automatic sequencing. The phenotypes of hereditary MTC were as follows: 7 MEN 2A, 3 MEN 2A associated with CLA, 3 MEN 2B, 2 FMTC and 1 other forms. We identified mutations at codon 634 in 6 families with MEN 2A, only one kindred had the mutation at codon 618. The 3 kindred with MEN 2A+CLA, both cases of FMTC and the only family classified as other hereditary forms of the MTC presented the mutation in codon 634. A mutation at codon M918T was identified in the 3 individuals with MEN 2B. The genetic screening was able to identified 23 assymtomatic carriers and determine the hereditary MCT pattern in 3 individuals with apparently sporadic tumors. In conclusion, genetic testing can identify affected and assymtomatic individuals with hereditary disease, allowing early diagnosis and treatment.