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Deletion of the second allele of the tumour suppressor gene MEN1 is assoiated with development of duodenal gastrin-secreting microtumours in MEN1
Zollinger–Ellison syndrome results from hypergastrinaemia and gastric hyperacidity. The disorder is clinically characterised by recurrent peptic ulcer disease, gastroesophageal reflux disease and, often...
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Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonheredi...
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited disorder, characterised by the occurrence of tumours of the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands and neuroendocrine carcinoid tumours. Carcinoid tumours of the thymus and pancreatic-duodenal gastrinomas are the most harmful...
Citations
... Nonetheless, a majority of PanNETs (>60%) do not have MEN1 mutations but still lose MEN1 expression (9)(10)(11). Similar to the role of KRAS in pancreatic cancer, MEN1 is believed to be a predominant driver gene and plays a critical role in PanNET initiation and progression (12)(13)(14)(15)(16)(17)(18)(19).Specifically, our previous study reported that overexpression of MEN1 inhibited mTOR activation and resulted in PanNET cell ferroptosis via the suppression of stearoyl-CoA desaturase (SCD1), and enhanced the PanNET cell response to everolimus(20). Another study found that MEN1 silencing in ER+ breast cancer cells led to mTOR activation by promoting the phosphorylation of p70S6K1, p85S6K1 and 4EBP1. ...
... MEN1 is located at chromosome band 11q13, where losses of heterozygosity (LOH) with somatic mutations of multiple driver genes often occur in a variety of sporadic endocrine tumors, such as pancreatic insulinomas and pancreatic neuroendocrine tumors (6,13). The in vivo study of MEN1-associated PanNETs is appreciable using MEN1-knockout mice model and clinical patient tissue samples. ...
Pancreatic neuroendocrine tumors (PanNET) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for patients with PanNET. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 was found in PanNET tissues compared with paired-adjacent tissues and was associated with poor prognosis in patients with PanNET. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacologic mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and to inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B–DCAF7 axis and identifies potential therapeutic targets in patients with MEN1-associated PanNET.
Significance
Identification of neddylation and ubiquitination pathways that regulate MEN1 protein stability provides an opportunity for therapeutic interventions for treating patients with pancreatic neuroendocrine tumors.
... As a result, a duodenal G-cell hyperplasia to neoplasia sequence was proposed (16). However, if MEN1 does not stack the odds against G-cells, what factor does (17,18)? ...
Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wildtype allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wildtype MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome related gastrinoma to biochemical prevention.
... The incidence of gastrinoma is estimated to be in the range of 0.5 to 4 new cases per year per million population [2]. Gastrinomas present either sporadically or associated with multiple endocrine neoplasms type 1 (MEN1), due to an autosomal dominant mutation in the MEN1 gene on chromosome 11q13 [3]. Gastrinomas usually arise in the pancreas and duodenum within the gastrinoma triangle, which defines the confluence of the cystic and common bile duct superiorly, the II and III portion of the duodenum inferiorly and the junction of the neck and body of the pancreas medially [4]; although gastrinomas may occur in both abdominal and extra-abdominal sites [5]. ...
Background:
Gastrinoma is a rare form of neuroendocrine neoplasm. The presence of a primary lymph node localization of gastrinoma is a much debated and controversial topic in the literature, as regards whether these cases represent metastatic disease from an as yet unidentified primary tumor, or the de novo occurrence of a gastrinoma in a lymph node.
Case presentation:
We report the case of a 24-year-old male with intense epigastric pain treated at the beginning with high dose proton pump inhibitors. Further workup with CT and subsequent laparotomy revealed a single peripancreatic lymph node. Histological examination highlighted a well-differentiated neuroendocrine tumor.
Conclusion:
This case underlines that the primitive lymph node gastrinoma is a distinct nosological entity with a precise location in the context of rare neuroendocrine tumors that should be considered when specific symptoms are associated with the identification of isolated lymph nodes, after excluding any possible primitive locations of neoplastic localization.
... Anlauf and his co-authors found that 13/28 (46.4%) duodenal gastrin-producing neuroendocrine tumors and 2/5 (40%) somatostatin-secreting neuroendocrine tumors revealed LOH of 11q13 from six patients with Zollinger-Ellison syndrome and MEN1 [23,24]. At the same time, none of the 12 precursor lesions showed LOH at the 11q13 locus. ...
Background:
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder arising from mutations of the MEN1 tumor suppressor gene on chromosome 11q13; MEN1 is characterized by the development of neuroendocrine tumors, including those of the parathyroid, gastrointestinal endocrine tissue and anterior pituitary. Additionally, thymic neuroendocrine tumors in MEN1 are also rarely reported.
Case presentation:
This case report observed a family that presented with MEN1 p.L105Vfs mutation, and two of the family members had been diagnosed with thymic neuroendocrine tumor combined with MEN1. To the best of our knowledge, this is the first time such a mutation in the MEN1 gene has been reported. The proband presented with thymic neuroendocrine tumor, parathyroid adenoma and rectum adenocarcinoma. The son of the proband presented with thymic neuroendocrine tumor, gastrinoma, hypophysoma and parathyroid adenoma. Genetic testing revealed the frameshift mutation p.L105Vfs, leading to the identification of one carrier in the pedigree (the patient's younger sister). The proband then underwent parathyroidectomy at the age of 26 years (in 1980) for a parathyroid adenoma. Subsequently, the patient underwent thymectomy, radiotherapy and chemotherapy. The patient is now 64 years old, still alive and still undergoing Lanreotide therapy.
Conclusion:
Thymic neuroendocrine MEN1 is rare, but it accounts for almost 20% of MEN1-associated mortality. Consequently, we should focus on regular clinical screening of the thymus in MEN1 patients.
... In addition, most gastrinomas do not display LOH 8,10,11 . This long-standing observation provides additional evidence supporting the likelihood that loss of menin function occurs by mechanisms other than by gene deletion 37 38,39 . However, due to their small size, scattered location and lack of experimental models, extensive mechanistic analysis of these tumors has been hampered. ...
Background & aims:
The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors (NETs) such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia.
Methods:
Primary enteric glial cultures were generated from the VillinCre:Men(1FL/FL):Sst(-/-) mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from VillinCre:Men1FL/FL:Sst(+/+) mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom.
Results:
Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells, e.g., p75 and S100B, colocalized with gastrin in human duodenal gastrinomas.
Conclusions:
MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.
... 17 Gastrinomas in patients with MEN1 tend to arise in the duodenum, can be quite small, associate with gastrin cell hyperplasias, and are frequently multiple. [19][20][21] These tumors produce gastrin and can lead to Zollinger-Ellison syndrome. Histologically, they comprise proliferations of monotonous neuroendocrine cells. ...
Multiple endocrine neoplasia (MEN) syndrome is a familial cancer syndrome characterized by neuroendocrine tumors. The syndrome encompasses four major subtypes: MEN1, MEN2A, MEN2B, and MEN4. MEN1 is caused by mutations in the MEN1 gene, MEN2A and MEN2B are caused by mutations in RET, and MEN4 is caused by mutations in CDKNB1. All are inherited in an autosomal dominant pattern, but de novo cases do arise. While all subtypes are associated with neuroendocrine tumors, each has characteristic organ involvement. Identifying patients with the syndrome can aid in proper screening and treatment.
... Loss of heterozygosity (LOH) at the MEN1 locus is present in adenomas as small as 0.3 mm in diameter, demonstrating that these microadenomas are true tumors according to Knudson's two-hit hypothesis of tumor development[26]. Interestingly, the exact pattern of LOH differs between microadenomas, suggesting that these microadenomas arise independently from the hyperplastic background[21],[27]–[29]. Because few clinical adenomas develop but numerous microadenomas are observed, additional mutations must accrue to form larger and clinically significant PNETs. ...
... It is not known whether these lesions are monoclonal. Although most of these lesions are not likely clinically significant, they could represent precursor lesions that give rise to sporadic PNETs because all clinical PNETs have to pass through a microadenoma stage during their growth[29]. It is therefore plausible that PNETs develop from precursor (pre-malignant) lesions, such as hyperplasia and microadenoma, in familial PNET syndromes and in some sporadic cases[29]. ...
... Although most of these lesions are not likely clinically significant, they could represent precursor lesions that give rise to sporadic PNETs because all clinical PNETs have to pass through a microadenoma stage during their growth[29]. It is therefore plausible that PNETs develop from precursor (pre-malignant) lesions, such as hyperplasia and microadenoma, in familial PNET syndromes and in some sporadic cases[29]. ...
Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are understood to some degree while the molecular pathogenesis of PNETs is still unclear. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is not readily predictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally portend less favorable prognosis. Endocrine testing, imaging, and histological evidence are needed for accurate diagnosis of PNETs. An "aggressive" treatment approach with 4 components: surgery, locoregional therapy, systemic therapy, and complication control, has becomes a trend in academic centers throughout the world. The optimal use of the multiple modalities of systemic therapy is still being developed; efficacy, safety, availability, and cost should be considered when treating a specific patient. Clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including a novel Mahvash disease, are summarized.
Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function, and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation in Cdkn1b (p27) and not in Men1. Both Men1-knockout mice and MENX rats have been exploited for therapy response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors.
