GENETIC TESTING IN MEDULLARY-THYROID CARCINOMA SYNDROMES - MUTATION TYPES AND CLINICAL-SIGNIFICANCE

Objective: To determine the types of mutations and the clinical signif icance of a specific genotype in familial medullary thyroid carcinoma (MTC) syndromes,Design: We retrospectively and prospectively studied p atients with MTC at a tertiary referral center, Material and Methods: The study cohort consisted of 348 affected patients and at-risk family members of MTC kindreds, including 33 multiple endocrine neoplasia ty pe IIA (MEN IIA) kindreds with 165 members, 13 familial MTC alone (FMT C) kindreds (at least 4 affected members with MTC per kindred, without evidence of pheochromocytoma and hyperparathyroidism) with 108 member s, 15 ''other hereditary MTC'' kindreds (2 or 3 affected members) with 42 members, and 33 individuals with sporadic MTC, An additional 53 su bjects from the aforementioned MEN IIA kindreds who were clinically af fected but not genetically tested were also included in an analysis of the relationship between genotype and phenotype, The presence of germ line mutations in the RET protooncogene was studied by DNA sequence an alysis of exons 10, 11, and 13. Results: Germline RET mutations in exo ns 10 and 11 were identified in 32 of 33 MEN IIA kindreds (97%), 10 of 13 FMTC kindreds (77%), and 10 of 15 ''other hereditary MTC'' kindred s (67%), No mutations were identified in exon 13, No patient with spor adic MTC had a germline mutation, In MEN IIA, codon 634 was affected i n 73% of the kindreds, whereas in FMTC, the main affected codon was co don 618 (54%), In MEN IIA, patients with codon 634 mutations had a hig her risk of having C-cell disease, pheochromocytoma, and hyperparathyr oidism than did those with other mutations (P < 0,05, P < 0,001, and P < 0.01, respectively), Conclusion: RET analysis is a reliable, practi cal, and cost-effective test in the screening of at-risk family member s of MEN IIB and FMTC kindreds, In addition, RET analysis mag be helpf ul in the follow-up of gene carriers and for the early detection of ph eochromocytoma and hyperparathyroidism in patients with codon 634 muta tions.