Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities

Abstract

The ground-breaking discovery of genotype-phenotype relationships in hereditary medullary thyroid cancer has greatly facilitated early prophylactic thyroidectomy. Its timing depends not solely on a positive gene test but, more importantly, on the type of the REarranged during Transfection (RET) mutation and its underlying mode of RET receptor tyrosine kinase activation. In the past decade, the therapeutic corridor opened by molecular information has been defined down to a remarkable level of detail. Based on mutational risk profiles, preemptive thyroidectomy is recommended at 6 months of age for carriers of highest-risk mutations, before the age of 5 years for carriers of high-risk mutations, and before the age of 5 or 10 years for carriers of least-high-risk mutations. Additional lymph node dissection may not be needed in the absence of increased preoperative basal calcitonin levels. Better comprehension of RET function should enable the design of targeted therapies for RET carriers beyond surgical cure in whom the DNA-based 'window of opportunity' has been missed.

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

“…A second mutation in one of these neuroendocrine cells ('second hit') is thought to cause MTC (C-cell cancer), pheochromocytoma or primary hyperparathyroidism due to multiple hyperplastic nodules in a pattern best defined as pseudonodular parathyroid hyperplasia. Because acquisition of somatic mutations by these cells reflects the play of chance, the development of the different MEN2 components varies even among members of the same family, compromising predictions by which age the various MEN2 components may become clinically apparent (Machens et al 2009b, Wells et al 2013. As a corollary, the weaker is the transforming activity of inherited RET mutations (genotype), the less complete tends to be the penetrance of the other MEN2-associated components (phenotype).…”

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

“…Owing to the rarity of the MEN 2 syndromes, the prevalence of the different RET mutations is not well defined, and it is not clear whether specific mutations are more prevalent in distinct geographic areas (21)(22)(23). So far, there are only four published European studies collecting data from several centres in which the prevalence and distribution of different RET mutations have been investigated (2,(23)(24)(25).…”

Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium

“…The RET gene encodes for the membrane-bound RET receptor tyrosine kinase, which is mainly expressed in neural crestderived cell lineages such as parafollicular C cells, adrenal medullary cells, and parathyroid chief cells (3). Clinically, MEN2 is subdivided into MEN type 2A (MEN2A), comprising medullary thyroid cancer (MTC), pheochromocytoma and primary hyperparathyroidism, and MEN type 2B (MEN2B).…”

“…Twenty years ago, the groundbreaking discovery that activating rearranged during transfection (RET) mutations in codons 609, 611, 618, 620, 630 (American Thyroid Association/ATA class B), 634 (ATA class C), and 918 (ATA class D) underlie multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid cancer (FMTC) ushered in the era of personalized medicine (1,2,3,4). The RET gene encodes for the membrane-bound RET receptor tyrosine kinase, which is mainly expressed in neural crestderived cell lineages such as parafollicular C cells, adrenal medullary cells, and parathyroid chief cells (3).…”