Activating mutations in thec-RET proto-oncogene causes Multiple Endocrine Neoplasia Type 2

The RET proto-oncogene encodes a receptor tyrosine kinase implicated in the pathogenesis of Multiple Endocrine Neoplasia Type 2 (MEN2), a syndrome of neuroendocrine tumor formation and disordered development that is comprised of three clinical subtypes MEN2A, MEN2B and FMTC (Familial Medullary Thyroid Carcinoma). MEN2A patients develop C cell hyperplasia/medullary thyroid cancer, parathyroid hyperplasia, and pheochromocytomas. MEN2B is similar except that ganglioneuromas, mucosal neuromas and marfanoid habitus occur in place of parathyroid hyperplasia. Interestingly, all three clinical subtypes were shown to be associated with mutations in RET.;Oncogenic activation of RET is thought to be due to ligand-independent stimulation of tyrosine kinase activity in MEN2A and FMTC, and to changes in substrate specificity of the kinase in MEN2B. In order to investigate the effects of these mutations on pre- and post-natal development, tumorigenesis and tumor progression, we utilized gene targeting techniques to produce mouse models of these syndromes. We have found that both the RETMEN2A and RETMEN2B mutations cause pre-neoplastic changes in murine thyroid C-cells, while RETMEN2B animals develop pheochromocytomas, ganglioneuromas and male reproductive defects. Unlike RET knockout mice, RET MEN2B homozygotes have normal kidneys and enteric nervous system, indicating that the mutation does not preclude normal developmental functions. Homozygotes exhibit more severe pathology that heterozygotes, with earlier onset of adrenal and thyroid hyperplasia/tumors and ganglioneuroma of the adrenal and sympathetic ganglia. Crosses between RETMEN2B and RET knockout mice indicated that the more severe pathology in RETMEN2B homozygotes; is due to a dosage affect of the mutant allele.;This murine model represents formal proof that MEN2B is a hereditary cancer that results from a dominantly activating mutation. We expect that it should facilitate further understanding of the developmental basis of medullary thyroid cancer, pheochromocytoma, ganglioneuroma, and male reproductive defects, including the effect of genetic background and the role of secondary mutations in tumorigenesis and progression. In addition, the model will be useful for the evaluation of new therapies.