MUTATIONS OF THE RET PROTOONCOGENE IN GERMAN MULTIPLE ENDOCRINE NEOPLASIA FAMILIES - RELATION BETWEEN GENOTYPE AND PHENOTYPE

It has been suggested that not only the position but also the nature o f the mutations of the ret protooncogene strongly correlate with the c linical manifestation of the multiple endocrine neoplasm type 2 (MEN 2 ) syndrome. In particular, individuals with a Cys(634)-Arg substitutio n should have a greater risk of developing parathyroid disease. We, th erefore, analyzed 94 unrelated families from Germany with inherited me dullary thyroid carcinoma (MTC) for mutation of the ret protooncogene. In all but 1 of 59 families with MEN 2A, germline mutations in the ex tracellular domain of the ret protein were found. Some 81% of the MEN 2A mutations affected codon 634. Phenotype-genotype correlations sugge sted that the prevalence of pheochromocytoma and hyperparathyroidism i s significantly higher in families with codon 634 mutations, but there was no correlation with the nature of the mutation. In all but 1 of 2 7 familial MTC (FMTC) families, mutations were detected in 1 of 4 cyst eines in the extracellular domain of the ret protooncogene. Half of th e FMTC mutations affected codon 634. Mutations outside of codon 634 oc curred more often in FMTC families than in MEN 2A families. In all but 1 of 8 MEN 2B patients, de novo mutations in codon 918 were found. Th ese data confirm the preferential localization of MEN 2-associated mut ations and the correlation between disease phenotype and the position of the ret mutation, but there was no correlation between the occurren ce of hyperparathyroidism or pheochromocytoma and the nature of the mu tation.