Deep Insight Section

Neuroendocrine tumors (NET) are uncommon diseases occuring sporadically or in a familial context of autosomal dominant inherited syndromes such as Multiple Endocrine Neoplasia (MEN). During the last decade, at least six major genes involved in initial steps of NET have been characterized and one would expect that clinical screening syndromic forms of NET will include now genetic studies as a common tool for presymptomatic diagnosis (Calender, 2000). Four major MEN syndromes are MEN1 MEN2, von Hippel Lindau disease (VHL), and Carney Complex (CC) which represent the most common forms of inherited predisposition to NET with variable but high penetrance of proliferations in various neuroendocrine tissues. Less commonly, endocrine tumors of the pancreas , parathyroids and adrenal glands have been observed in phacomatosis such as Recklinghausen disease (NF1), Tuberous sclerosis (TSC). Lastly, familial occurrence of a single endocrine lesion, such as primary hyperparathyroidism or pituitary adenoma have been identified as putative new genetic diseases fo which genetic pathways remain to be identified. Most NET predisposing diseases were related to inactivation of growth suppressor genes, according to the Knudson model, except MEN2, an inherited form of medullary thyroid carcinoma, which occur through dominant activation of a proto-oncogene, the RET tyrosine kinase receptor. Nevertheless, recent knowledges on the biological roles of most genes involved in cancer predisposition teaches us that a single gene might have pleiotropic effects at various stages of the cell physiology as for instance both a negative and a positive regulator function depending on the cellular context and sometimes the type of mutation (Zheng et al., 2000). Cloning of genes involved in genetic diseases predisposing to NET has led to a better insight in the molecular nature of tumor initiation of (neuro) endocrine tissues in most endocrine glands. Even if the genes and related syndromes are presented separately, we would expect that genetic studies in patients with NET will now help to the differential diagnosis of syndromic diseases and that a single type of endocrine tumor may be related to the deregulation of distinct genes and related pathways. Major syndromes predisposing to NET and overlapping symptoms leading in some patients and/or families to adress the differential diagnosis by molecular genetic tools are presented in Figure 1.