EARLY DIAGNOSIS OF MULTIPLE ENDOCRINE NEO PLASIA TYPE-2 BY DETECTION OF MUTATED RET PROTOONCOGENE CARRIERS

RET proto-oncogene mutation results in a dominant autosomic inherited syndrome (MEN 2) presenting three distinct subtypes: MEN 2A, MEN 2B, a nd familial medullary thyroid carcinoma (FMTC). Detection of RET proto -oncogene mutation is a predictor before clinical or biochemical evide nce of the disease is present and leads to preventive thyroid removal since there is no effective treatment for metastases. The aim of the p resent study was to characterize mutations in the RET proto-oncogene i n affected patients and to identify potential carriers in their famili es. Two families with FMTC (5 and 6 members), 4 with MEN 2A (5, 5, 4 a nd 3 members) and 2 with MEN 2B (5 and 1 members), were studied. DNA w as obtained from blood samples in all patients and from thyroid or fro m pheochromocytoma tissues in patients submitted to surgery. PCR ampli fication was performed using specific primers for exons 10, 11 and 16, followed by direct sequencing. Mutations at codon 634 in exon II were found in 16 subjects with FMTC and MEN 2A: TGC --> CGC ((cysteine to arginine) in 9 cases, TGC --> TAC (cysteine to tyrosine) in 3, and TGC --> TTC (cysteine to phenilalanine) in 4. A unique mutation at codon 918 in exon 16, ATG --> ACG (methionine to threonine), was found in bo th MEN 2 B affected patients. The mutations detected in DNA from perip heral blood were the same as those present in DNA extracted from tumor material. RET mutations were detected in all affected patients, confi rming the diagnosis, and in 10 members of their families. in five of t he carriers total thyroidectomy was performed. Anatomopathological stu dy showed C-cells hyperplasia or in-situ microcarcinoma in two childre n (9 and 12 y) with no clinical signs of disease and medullary thyroid carcinoma in three adults, who were previously unaware of the presenc e of thyroid nodules. The early detection of RET mutation followed by total thyroidectomy may prevent the development of the disease, specia lly in affected families, and avoid the fatal outcome of delayed medul lary thyroid carcinoma diagnosis.