Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)".

Germline and somatic mutations of the RET proto-oncogene are important pathogenetic factors in hereditary and sporadic forms of medullary thyroid carcinoma (MTC). We have therefore analysed exons 10, 11, 13, 14 and 16 of this gene in 85 individuals from 16 Austrian families who, according to clinical criteria, were at risk of suffering from hereditary forms of MTC. We found mutations (codons 620,634 and 804) in the germline of 3 families with familial medullary thyroid carcinoma (FMTC), of 5 with multiple endocrine neoplasia type 2A (MEN 2A; codon 634) and of 2 with multiple endocrine neoplasia type 2B (MEN 2B; codon 918). The codon 804 mutation in one FMTC family led to the substitution of Val (GTG) for Met (ATG) and has not been reported previously. Within these 10 families, 32 carriers and 32 non-carriers were identified. Somatic mutations in the tumors of 3 other families suggested a sporadic origin of the neoplasms. In the remaining 3 families, no mutations were identified. Fifty-nine individuals with an apparently sporadic MTC lacked germline mutations in the RET gene, whereas 7 of 24 available tumors (29%) contained a somatic mutation in codon 918. Our findings provide further evidence that molecular genetic evaluation of hereditary and sporadic forms of MTC is a necessary prerequisite for counselling and management of patients and their families.