MEN1 is an autosomal dominant syndrome resulting from an inactivating germline mutation of the MEN1 gene located on chromosome 11q13 .
Up to 80% of MEN1-associated tumors exhibit loss of heterozigosity (LOH) of 11q13, indicating that MEN1 functions as a tumor suppressor gene.
Approximately 21% of sporadic pancreatic neuroendocrine tumors (PNETs) harbour mutations in MEN1, but there is substantial variation across different tumor subtypes. Whereas only 8% of insulinomas and non-functioning PNETs have identifiable MEN1 mutations, they are more frequent in gastrinomas [37%), VIPomas (44%) and glucagonomas (67%) [24-31].In contrast to the relatively low frequency of MEN1 mutations in sporadic PNETs, up to 68% display LOH at chromosome 11q13 .
This raises the possibility there may be other, yet to be identified, tumor suppressor genes on the long arm of chromosome 11. Similarly, LOH of chromosome 11 is present in up to 78% of gastrointestinal carcinoids, but the frequency of MEN1 mutations is much lower. Gortz et al. reported MEN1 mutations in 2/11 (18%) gastrointestinal carcinoids and 2/11 [18%) lung carcinoids  and Debelenko et al identified MEN1 mutations in 4/11 (36%) lung carcinoids . The MEN1 gene product, menin, is a nuclear protein that binds to many transcription factors, including the AP1 component JunD. Upon binding to JunD, menin represses JunD-mediated transcription to inhibit cellular proliferation. Inactivating mutations of MEN1 disrupt the binding to JunD to enhance transcription and augment cellular proliferation [34, 35]. More recently, menin was also identified in a complex with the MLL histone methyltransferase that associates with regulatory elements in the promoters of the cell cycle inhibitors p27KIP1 and p18Ink4c to methylate histone H3 and enhance gene transcription . In mouse models, the absence of Men1 results in down-regulation of p27KIP1 and p18Ink4c and a phenotype resembling the MEN1 syndrome, including islet-cell hyperplasia [37, 38].
Of note, a similar phenotype was also observed in p27KIP1/p18Ink4c double-mutant mice suggesting that deregulation of the cell cycle may be the critical consequence of MEN1 mutations and a necessary feature of NET pathogenesis in general . Recently, the telomerase (hTERT) gene was identified as a menin target gene. The end of chromosome in a cell, shorten after DNA replication. Eventually, after several cell divisions, the DNA loses its stability and the cell is subjected to apoptosis. Telomerase is an enzyme that maintains the length of the telomeres and is not expressed in normal cells, but it is active in stem cells and tumor cells. Menin is a suppressor of the expression of the telomerase gene. Possibly, inactivation of menin could lead to cell immortalization by telomerase expression, which could allow a cell to develop into a tumor cell .
In approximately 10-15% of patients with a clinical diagnosis of MEN1 is not possible to identify a known mutation, due to the presence of regulatory sequences inactivated. In such cases the genetic analysis of first-degree relatives of patients with apparently negative family history can be helpful in identifying possible new mutations .
MEN2 is dominantly inherited, and its genetic cause, mutations of the REarranged during Transfection (RET) protooncogene, was first recognized nearly 20 years ago [10, 42-44].
Since then, the range of mutations identified, their potential for predicting clinical course, and the underlying functional effects have been explored. Detection of RET mutations in MEN2 represents a paradigm for genetically guided patient management, and genotype–phenotype correlations in this disease now inform recommended interventions, patient and family screening, and long-term follow-up [10, 45].
The RET proto-oncogene encodes a receptor tyrosine kinase that is required for the development of neural-crest derived cells, the urogenital system, and the central and peripheral nervous systems, notably the enteric nervous system [46, 47].
The RET protein has a large extracellular domain containing a cysteine-rich region and a series of cadherin homology domains, a transmembrane domain, and an intracellular tyrosine kinase domain, required for RET phosphorylation and downstream signalling [48, 49].
The RET kinase is structurally similar to other tyrosine kinases, sharing many conserved functional motifs and regulatory residues that have been shown to have importance for kinase enzyme function . RET is activated by binding of a multi-protein ligand complex. RET binds a soluble ligand of the glial cell-line-derived neurotrophic factor (GDNF) family but also requires a co-receptor of the GDNF family receptors a (GFRa), which is tethered to the cell membrane via glycosylphosphatidylinositol linkage [51, 52]. Initially, GDNF binds to GFRa, and these complexes are then able to recruit RET to form heterohexamers that are concentrated in regions of the cell membrane called lipid rafts These are membrane domains enriched in glycosylphosphatidylinositol-linked proteins and signaling molecules that provide a platform not only for enhanced cell signaling, but also for regulation of receptor kinase activity and down-regulation .
Activation of RET leads to stimulation of multiple downstream pathways, including mitogen-activated protein kinase and extracellular signal-regulated kinase, phosphoinositide 3-kinase and protein kinase B, signal transducer and activator of transcription 3, proto-oncogene tyrosine-protein kinase Src1, and focal adhesion kinase that promote cell growth, proliferation, survival, and/or differentiation [54, 55].
MEN2 is associated with point mutations of RET, predictably leading to its activation in the absence of ligands and co-receptors. Mutations are primarily amino acid substitutions affecting a very small number of RET codons in either the extracellular domain or within the kinase domain.
Mutations are dominant, requiring only a single mutant allele to confer the disease phenotype. MEN2 RET mutation occurrence [56-59] are available online (http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php). Together, these data suggest strong overall themes as to functional effects of these mutations, but also as to their clinical significance.
Together, these data suggest strong overall themes as to functional effects of these mutations, but also as to their clinical significance. Strong associations of disease subtype, and also specific disease phenotypes, with individual RET mutations have made it possible to stratify risk of MEN2 by genotype [10, 45].
The management guidelines of the American Thyroid Association base the recommendations for initial diagnosis, therapeutic intervention, and long-term follow-up on patient genotype and the current understanding of the natural history of the disease associated with each RET mutation. Mutations of cysteine residues (primarily cysteines 609, 611, 618, 620, 630, and 634] in the RET extracellular domain account for the majority of MEN2A cases, and are also common in patients with FMTC. Intracellular kinase domain mutations are mainly associated with FMTC and MEN2B. Mutations in the intracellular codons 768, 790, 791, 804, and 891 underlie FMTC, and occur less commonly in patients with MEN2A  while specific mutations of codon 918 (M918T) or 883 (A883F) account for the vast majority of MEN2B cases, and are exclusive to the subtype .
In addition to association with disease subtype, significant correlations of specific mutations with disease features are reported. For example, RET codon 634 mutations carry a greater patient risk for pheochromocytoma and parathyroid hyperplasia [62-64] and are associated with a higher frequency of detection of MTC at the time of early thyroidectomy .
Variation in clinical presentation has even been observed with different codon 634 substitutions. The specific substitution of an arginine at codon 634 (C634R) is strongly associated with increased risk of parathyroid hyperplasia increased frequency of distant metastases, earlier onset of both lymph node and distant metastases, and bilaterality of pheochromocytoma [66, 67].