Molecular genetics of neuroendocrine tumors

Through insights into the molecular genetics of neuroendocrine tumors (NETs ), the genes predisposing to multiple endocrine neoplasia (MEN) syndromes w ere identified. In MEN1, tumors occur in the parathyroids, endocrine pancre as, anterior pituitary, adrenal glands and thymic neuroendocrine tissues. T he MEN1 gene encodes a putative growth-suppressor protein, menin, binding J unD, a transcriptional factor belonging to the AP-1 complex. However, new p artners binding menin remain to be found. The MEN1 gene might be involved i n 1-50% of sporadic NETs. Another critical mechanism involved in NETs is th e deregulation of the RET-signalling pathways by oncogenic point mutations responsible for MEN2 syndromes. MEN2 refers to the inherited forms of medul lary thyroid carcinoma. The RET proto-oncogene, a tyrosine-kinase receptor, is activated by missense mutations occurring either in the extracellular d imerization domain or intracellular tyrosine kinase catalytic regions. in b oth cases the receptor is constitutionally activated in the absence of natu ral ligands. Endocrine tumors also belong to the clinical pattern of Reckli nghausen (NF1) and von Hippel-Lindau (VHL) diseases. The genes for both syn dromes have been characterized and provide new pathways for endocrine tumor igenesis related to G-protein physiology (NF?)and transcriptional regulatio n and/or endothelial cell proliferation (VHL), respectively. Here, we propo se a basic overview of recent data on genetic events leading a normal endoc rine cell towards a fully malignant phenotype. Copyright (C) 2000 S. Karger AG, Basel.