ACTIVATION OF RET AS A DOMINANT TRANSFORMING GENE BY GERMLINE MUTATIONS OF MEN2A AND MEN2B

Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and fam ilial medullary thyroid carcinoma are dominantly inherited cancer synd romes. All three syndromes are associated with mutations in RET, which encodes a receptor-like tyrosine kinase. The altered RET alleles were shown to be transforming genes in NIH 3T3 cells as a consequence of c onstitutive activation of the RET kinase. The MEN2A mutation resulted in RET dimerization at steady state, whereas the MEN2B mutation altere d RET catalytic properties both quantitatively and qualitatively. Onco genic conversion RET in these neoplastic syndromes establishes germlin e transmission of dominant transforming genes in human cancer.