Molecular genetics of neuroendocrine tumors

Through insights into the molecular genetics of neuroendocrine tumors (NETs), the genes predisposing to multiple endocrine neoplasia (MEN) syndromes were identified. In MEN1, tumors occur in the parathyroids, endocrine pancreas, anterior pituitary, adrenal glands and thymic neuroendocrine tissues. The MEN1 gene encodes a putative growth-suppressor protein, menin, binding JunD, a transcriptional factor belonging to the AP-1 complex. However, new partners binding menin remain to be found. The MEN1 gene might be involved in 1-50% of sporadic NETs. Another critical mechanism involved in NETs is the deregulation of the RET-signalling pathways by oncogenic point mutations responsible for MEN2 syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma. The RET proto-oncogene, a tyrosine-kinase receptor, is activated by missense mutations occurring either in the extracellular dimerization domain or intracellular tyrosine kinase catalytic regions. In both cases the receptor is constitutionally activated in the absence of natural ligands. Endocrine tumors also belong to the clinical pattern of Recklinghausen (NF1) and von Hippel-Lindau (VHL) diseases. The genes for both syndromes have been characterized and provide new pathways for endocrine tumorigenesis related to G-protein physiology (NF1) and transcriptional regulation and/or endothelial cell proliferation (VHL), respectively. Here, we propose a basic overview of recent data on genetic events leading a normal endocrine cell towards a fully malignant phenotype.