Mutations of ret-proto-oncogene in thyroid medullary carcinoma

OBJECTIVE: To determine the importance of the molecular-genetic demonstration of germ-line mutation in the ret protooncogene for therapeutic measures in sporadic and hereditary medullary thyroid carcinoma (MTC). PATIENTS AND METHODS: Several molecular-genetic tests were performed on DNA of 35 families with hereditary and 81 patients with the sporadic form of MTC (isolation of genomic DNA; PCR amplification; DNA sequencing: demonstration of mutation in codon 918 with restriction enzyme FOK 1). RESULTS: A disease risk was demonstrated in 178 individuals among the 35 families, 159 of whom were investigated by molecular-genetic tests: 84 family members were found to be gene carriers. Germ-line mutation had already been suspected on clinical grounds in 76% of the carriers, 24% being discovered in a presymptomatic stage. Six children among the latter were treated prophylactically by thyroidectomy, histological evidence of C-cell hyperplasia being found in all of them, microcarcinomas in three of the older children. There were four patients among the non-carriers on whom thyroidectomy had been performed previously because of a false-positive pentagastrin-test; but germ-line mutation was now excluded. In one family, with familial MTC in two brothers, no mutation in ret-proto-oncogene has been demonstrated. The members of this family must now, as used to be routine, undergo a pentagastrin-test. Three of the 81 patients with "sporadic" MTC had a germ-line mutation, presumably a new one. CONCLUSION: Molecular-genetic tests have further improved the management of families with hereditary MTC and they thus take first place among essential diagnostic procedures. The diagnosis of sporadic MTC can be confirmed by excluding germ-line mutation in the ret-proto-oncogene.