Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC

Abstract

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the RET proto-oncogene. Three distinct clinical subtypes of MEN 2 have been characterized: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). 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 prophylactic thyroidectomy and extent of surgery are based on classification of RET mutations into risk levels according to genotype-phenotype correlations. The excellent prognosis for MTC diagnosed at its earliest stage underscores the importance of prospective screening (calcitonin screening) for sporadic MTC and early diagnosis by RET-mutation analysis for hereditary MTC. MEN 2 provides a unique model for early prevention and cure of cancer and for the roles of stratified mutation-based diagnosis and therapy of carriers.