RESUMO
BACKGROUND: Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by MTC only (FMTC) or coexistence of MTC with other endocrine neoplasia (NEM 2A, 2B). Germline mutations of the RET proto-oncogene (cRet) are found in the inherited forms and in some apparently sporadic MTC cases. AIM: To study RET mutations in 8 families with MEN 2. MATERIAL AND METHODS: RET mutations were screened in peripheral blood DNA from 18 patients and 87 high risk carriers belonging to 8 MEN 2 families and 52 sporadic MTC. Exons 10, 11, 13, 14, 15 and 16 of the c-Ret were amplified by polymerase chain reaction (PCR) and examined by direct sequencing of PCR products and/or restriction enzyme analysis. RESULTS: Five MEN 2A and one FMTC families with a germline mutation at codon 634, one MEN 2A and one FMTC family carrying a mutation at codon 620 were identified. Mutations were found in 23 out of 87 high risk carriers. In addition, we detected a S891A (exon 15) germline mutation in a sporadic MTC patient and in one out of her three sons and V804M (exon 14) in another sporadic MTC case and in one out of his six relatives, indicating in both cases the presence of a sporadic misclassified familial disease. CONCLUSIONS: These results underscore the importance of routine application of c-Ret testing in all cases of MTC either familial or sporadic.
Assuntos
Proteínas de Drosophila , Mutação em Linhagem Germinativa/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Sequência de Bases , Pré-Escolar , Chile , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Análise de Sequência de Proteína , Neoplasias da Glândula Tireoide/complicaçõesRESUMO
Hereditary medullary thyroid carcinoma is inherited as an autosomal dominant trait; at birth each child of an affected parent has a 50% chance of developing the disease. Measurement of plasma calcitonin concentrations after provocative calcium or pentagastrin stimulation has proved useful in the early diagnosis of this disease. To determine the age-related risk of conversion from a negative to a positive provocative test, 445 members of 11 kindreds were studied with sequential tests. Of 159 family members with a 50% risk at birth of developing medullary thyroid carcinoma 38 converted from a negative to a positive test result (mean age of conversion was 15 years). By means of methods previously described for determining the age-related probability for developing Huntington chorea, we present a method for determining the probability of development of medullary thyroid carcinoma. An individual at risk whose test result was negative had the following probability of converting to a positive test result at a later date: age (years)/probability, 0/0.5; 5/0.49; 10/0.41; 15/0.25; 20/0.16; 25/0.10, 30/0.05; and 35/0. We conclude that hereditary medullary thyroid carcinoma is regularly detectable in the pediatric age group and that screening should begin by age 5 years and be continued at regular intervals until age 35.