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a Department of
Pathology, Queen's University, Kingston, Ontario K7L 3N6, Canada, b Department of Paediatrics, Queen's University,
20 Barrie Street, Kingston, Ontario K7L 3N6, Canada
Correspondence to: Dr Mulligan, mulligal{at}post.queensu.ca
Multiple endocrine neoplasia type 2 (MEN 2) is an inherited
cancer syndrome characterised by medullary thyroid carcinoma (MTC), with or without phaeochromocytoma and hyperparathyroidism. MEN 2 is
unusual among cancer syndromes as it is caused by activation of a
cellular oncogene, RET. Germline mutations
in the gene encoding the RET receptor tyrosine kinase are found in the
vast majority of MEN 2 patients and somatic
RET mutations are found in a subset of
sporadic MTC. Further, there are strong associations of
RET mutation genotype and disease phenotype
in MEN 2 which have led to predictions of tissue specific requirements
and sensitivities to RET activity. Our ability to identify genetically,
with high accuracy, subjects with MEN 2 has revolutionised our ability
to diagnose, predict, and manage this disease. In the past few years, studies of RET and its normal ligand and downstream interactions and
the signalling pathways it activates have clarified our understanding of the roles played by RET in normal cell survival, proliferation, and
differentiation, as well as in disease. Here, we review the current
knowledge of the normal functions of RET and
the effects of mutations of this gene in tumorigenesis and in normal development.
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