Molecular pathogenesis of MEN2-associated tumors

Although the gene responsible for multiple endocrine neoplasia type 2 (MEN2) was discovered many years ago, the exact mechanisms of tumor development in patients affected with RET germline mutations remain unknown. In vitro studies have certain pitfalls, one of which is the use of cell culture systems such as the NIH3T3 cells, in which RET usually is not expressed in contrast to the in vivo situation. Recent data suggest that an overrepresentation of mutant RET as a 'second hit' event might trigger tumorigenesis. However, alterations in other genes might contribute to this overrepresentation of RET or impact on MEN 2-related tumor development through completely different mechanisms and pathways. The final goal of further elucidating the natural history and pathogenesis of MEN2-related tumors should be the chance to offer patients with RET germline mutations an optimal cancer prevention (e.g. codon specific recommendations for prophylactic thyroidectomy) and treatment program, especially for metastatic medullary thyroid carcinoma for which presently no effective therapy other than surgery exists.