The RET proto-oncogene in human cancers

The activation of the RET proto-oncogene contributes to the development of human cancers in two different ways. Somatic rearrangements of RET with a v ariety of activating genes, which contribute to unscheduled expression and constitutive dimerization of the chimeric RET/PTC oncoproteins in thyroid f ollicular cells, are frequently found in radiation-induced papillary thyroi d carcinomas. Germ-line mutations, mainly point mutations, that lead to con stitutive activation of RET tyrosine kinase activity are responsible for th e development of the inherited cancer syndrome, multiple endocrine neoplasi a type 2, There appears to be a correlation between specific types of RET m utation and clinical phenotypes of the cancers involved. The biological eff ects and the signaling pathways induced by different forms of RET activatio n have been investigated in a variety of cultured cells as well as in genet ically engineered animal models. The identification of RET mutations in mos t MEN 2 families (95%) has translated into improved care for MEN 2 patients . However, further investigation of the signaling pathways contributing to tumorigenesis in relevant tissues will eventually help us to develop no, el strategies to prevent or to treat human papillary thyroid carcinomas, MEN 2 disease, as well as the sporadic cancers relevant to MEN 2 disease.