Molecular Genetics of MEN2-Related Neuroendocrine Tumours

Abstract

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome with medullary thyroid carcinoma (MTC) as a common manifestation. It is caused by germline missense gain-of-function mutations of the RET proto-oncogene. Two distinct clinical subtypes of MEN2 have been characterized: MEN2A and MEN2B. The specific RET mutation may suggest a predilection toward a particular phenotype and clinical course, with strong genotype–phenotype correlations. Recommendations on the timing of early thyroidectomy and extent of surgery are based on classification of RET mutations into risk levels according to genotype–phenotype correlations as well as on penetrance and aggressiveness of MTC. The excellent prognosis for MTC diagnosed at its earliest stage underscores the importance of prospective calcitonin screening for sporadic MTC and early diagnosis by RET mutation analysis for hereditary MTC. MEN2 provides a unique model for early prevention and cure of cancer and for the roles of stratified mutation-based diagnosis and therapy of carriers. Understanding the molecular basis of both hereditary and sporadic MTC has led to the development of targeted therapy with tyrosine kinase inhibitors.