Endocrine Abstracts

The RET proto-oncogene, located on chromosome 10q11.2 encodes a receptor tyrosine kinase. Its extracellular portion contains four cadherin-like repeats and a cysteine-rich region, while the intracellular portion contains the tyrosine kinase domain. RET is essential for development of the sympathetic, parasympathetic and enteric nervous systems and the kidney. Accordingly, RET disruption by germline mutations causes congenital agangliosis of the gastrointestinal tract (Hirschsprung’s disease). The RET protein is a subunit of a multimolecular complex that binds growth factors of the glial-derived neurotropic factor (GDNF) family, including GDNF, neurturin, artemin and persephin. They bind RET in conjunction with glycosyl-phosphatidylinositol-anchored co-receptors (GFRα1-4), leading to the receptor dimerization and triggering autophosphorylation and intracellular signalling. RET mutations are responsible for the development of several human diseases, including multiple endocrine neoplasia 2A and 2B (MEN2A and MEN2B), familial medullary thyroid carcinoma (FMTC), papillary thyroid carcinoma and Hirschsprung’s disease. Most MEN2A and FMTC mutations affect cysteines in the extracellular cysteine-rich domain of RET. MEN2A is typically associated with mutations of codon 634, whereas FMTC is associated with mutations distributed among the various cysteines or in the RET kinase domain. Most MEN2B patients carry the M918T mutation in the RET kinase domain. Rarely, somatic deletions and germline duplications of variable segments of the gene have been reported in sporadic MTC and in FMTC. The mechanism leading to RET oncogenic activation depends on the site of the mutation. RET cysteine mutants form covalent dimers, due to the creation of intermolecular bonds, that display constitutive kinase activity. Differently, a change in substrate specificity has been implicated in the M918T MEN2B mutation. The high incidence of detectable mutations and the small number of target codons facilitate predictive and diagnostic testing. Indeed, soon after the identification of RET as the disease-gene, the genetic testing was introduced and it is now considered the standard of care for MEN2.