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Departments of Endocrinology, Surgical Oncology and Genetics University Medical Center Groningen, University of Groningen, The Netherlands; Department of Endocrinology University Medical Center Utrecht, The Netherlands
* To whom correspondence should be addressed. E-mail: r.m.w.hofstra{at}medgen.umcg.nl.
The RET gene encodes a receptor tyrosine kinase which is expressed in neural crest derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and non-inherited diseases. Germline point mutations are found in the cancer sydromes multiple endocrine neoplasia type 2 (MEN 2), including MEN 2A and 2B, and familial medullary thyroid carcinoma (FMTC). These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and FMTC and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas (PTCs). These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in pre-clinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.
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