Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice

Multiple endocrine neoplasia type 2B (MEN 2B) is a familial cancer syndrome , in which the cardinal feature is medullary thyroid carcinoma (MTC), a mal ignant tumor arising from the calcitonin producing thyroid C-cells, MEN 2B is associated with a germline point mutation in the RET proto-oncogene, lea ding to a Met-->Thr substitution at codon 918 in the kinase domain, which a lters the substrate specificity of the protein. we used the human calcitoni n gene (CALC-1) promoter to generate transgenic mice expressing either the human RET oncogene with the MEN2B-specific 918 Met-->Thr mutation (CALC-MEN 2B-RET) or the human nonmutated RET proto-oncogene (CALC-WT-AET) in the C-c ells, At 20-22 months of age three out of eight CALC-MEN2B-RET transgenic f ounders presented with macroscopic bilateral MTC, In two founders nodular C -cell hyperplasia (CCH) was observed. Thyroid abnormalities were never obse rved in CALC-WT-RET transgenic mice or control non-transgenic mice analysed at this age. In some mice from established CALC-MEN2B-RET transgenic lines nodular CCH was observed from 8 months on whereas MTC was detected in 13% of mice from one CALC-MEN2B-RET line, from the age of 11 months on. These r esults show for the first time that the MEN2B mutation in the RET oncogene predisposes mice for MTC.