Gene Summary

Gene:MEN1; menin 1
Aliases: MEAI, SCG2
Summary:This gene encodes menin, a putative tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. In vitro studies have shown menin is localized to the nucleus, possesses two functional nuclear localization signals, and inhibits transcriptional activation by JunD, however, the function of this protein is not known. Two messages have been detected on northern blots but the larger message has not been characterized. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 09 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MEN1 (cancer-related)

Backman S, Norlén O, Eriksson B, et al.
Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing.
Anticancer Res. 2017; 37(2):705-712 [PubMed] Related Publications
Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.
PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.
RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.
CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

Li Y, Peng Y, Jiang X, et al.
Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome.
Eur J Endocrinol. 2017; 176(2):187-194 [PubMed] Related Publications
OBJECTIVE: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing.
DESIGN AND METHODS: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform.
RESULTS: We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1-24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors.
CONCLUSIONS: Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.

Kwon EB, Jeong HR, Shim YS, et al.
Multiple Endocrine Neoplasia Type 1 Presenting as Hypoglycemia due to Insulinoma.
J Korean Med Sci. 2016; 31(6):1003-6 [PubMed] Free Access to Full Article Related Publications
Multiple endocrine neoplasia (MEN) mutation is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. The incidence of insulinoma in MEN is relatively uncommon, and there have been a few cases of MEN manifested with insulinoma as the first symptom in children. We experienced a 9-year-old girl having a familial MEN1 mutation. She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. At first, she was only diagnosed with insulinoma by abdominal magnetic resonance images of a 1.3 x 1.5 cm mass in the pancreas and high insulin levels in blood of the hepatic vein, but after her father was diagnosed with MEN1. We found she had familial MEN1 mutation, and she recovered hyperinsulinemic hypoglycemia after enucleation of the mass. Therefore, the early genetic identification of MEN1 mutation is considerable for children with at least one manifestation.

Melo FM, Couto PP, Bale AE, et al.
Whole-exome identifies RXRG and TH germline variants in familial isolated prolactinoma.
Cancer Genet. 2016; 209(6):251-7 [PubMed] Related Publications
Familial isolated pituitary adenoma (FIPA) is a rare genetic disorder. In a subset of FIPA families AIP germline mutations have been reported, but in most FIPA cases the exact genetic defect remains unknown. The present study aimed to determine the genetic basis of FIPA in a Brazilian family. Three siblings presented with isolated prolactin genes. Further mutation screening was performed using whole-exome sequencing and all likely causative mutations were validated by Sanger sequencing. In silico analysis and secreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate prolactinoma-mutated additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole-exome sequencing of three affected siblings revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. In conclusion, the RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family. The possible contribution of these genes to additional FIPA families should be explored.

Peculis R, Balcere I, Rovite V, et al.
Polymorphisms in MEN1 and DRD2 genes are associated with the occurrence and characteristics of pituitary adenomas.
Eur J Endocrinol. 2016; 175(2):145-53 [PubMed] Related Publications
OBJECTIVE: Although pituitary adenomas (PAs) affect a significant proportion of the population, only a fraction have the potential to become clinically relevant during an individual's lifetime, causing hormonal imbalance or complications due to mass effect. The overwhelming majority of cases are sporadic and without a clear familial history, and the genotype-phenotype correlation in PA patients is poorly understood. Our aim was to investigate the involvement of genes known for their role in familial cases on drug response and tumor suppression in the development and pathology of PAs in a patient group from Latvia.
DESIGN: The study included 143 cases and 354 controls, we investigated the role of single-nucleotide polymorphisms (SNPs) in seven genes (SSTR2, SSTR5, DRD2, MEN1, AIP, GNAS, and PRKAR1A) associated with pituitary tumor occurrence, phenotype, and clinical symptoms.
METHODS: Genotyping of 96 tag and nonsynonymous SNPs was performed in the genomic regions of interest.
RESULTS: We discovered a significant association (OR=17.8, CI 0.95=2.18-145.5, P=0.0002) between a rare MEN1 mutation (rs2959656) and clinically active adenoma in our patients. Additionally, rs7131056 at DRD2 was associated with a higher occurrence of extrasellar growth in patients with prolactinoma and somatotropinoma (OR=2.79, CI 0.95=1.58-4.95, P=0.0004).
CONCLUSIONS: rs2959656, a nonsynonymous variant in MEN1, is associated with the development of clinically active PA. Furthermore, rs7131056 in DRD2 contributes to either faster growth of the adenoma or reduced symptomatic presentation, allowing PAs to become larger before detection.

Crona J, Skogseid B
GEP- NETS UPDATE: Genetics of neuroendocrine tumors.
Eur J Endocrinol. 2016; 174(6):R275-90 [PubMed] Related Publications
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

Benafif S, Eeles R
Diagnosis and Management of Hereditary Carcinoids.
Recent Results Cancer Res. 2016; 205:149-68 [PubMed] Related Publications
Carcinoid tumours arise in cells of the diffuse neuroendocrine system and can develop in a number of anatomical sites including the lungs and the gastrointestinal tract. There has been a move away from the use of the term carcinoid tumour to the more appropriate use of neuroendocrine tumour (NET) to highlight the potential for invasion and metastasis associated with some NETs. Although most cases are sporadic, 15-20% of cases are related to a hereditary syndrome, the most common of these being multiple endocrine neoplasia 1 (MEN1). Other hereditary syndromes include the following: von Hippel-Lindau (VHL), neurofibromatosis 1 and tuberous sclerosis complex (TSC), which are all associated with a germline mutation of the associated tumour suppressor gene and an autosomal dominant inheritance pattern. Familial small intestinal NET (SI NET) is a recently described condition which is also inherited in an autosomal dominant manner. There appears to be more than one causative gene; thus far, only the IPMK gene has been identified as a causative germline mutation. This was identified by carrying out whole-exome sequencing of germline and tumour DNA in a family with multiple members diagnosed with SI NET. Identification of NET predisposition genes in other families via these methods will allow the development of dedicated NET gene panels which can be used to screen NET patients and at-risk relatives for hereditary mutations. Close surveillance of at-risk individuals is important to detect NETs early when curative surgery can be offered and the morbidity and mortality of metastatic NETs can be avoided.

Kim JH, Baddoo MC, Park EY, et al.
SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.
Mol Cell. 2016; 61(6):859-73 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

Minnetti M, Grossman A
Somatic and germline mutations in NETs: Implications for their diagnosis and management.
Best Pract Res Clin Endocrinol Metab. 2016; 30(1):115-27 [PubMed] Related Publications
It is now understood that specific somatic and germline mutations may lead to the development of the neuroendocrine tumours (NETs). NETs usually occur as sporadic isolated tumours, although they also may present as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), Von Hippel-Lindau (VHL) and neurofibromatosis syndromes, tuberous sclerosis, Carney triad and dyad, Reed syndrome and polycythaemia-paraganglioma syndromes. Only in MEN2 syndrome is there a specific genotype-phenotype correlation, although in both sporadic and syndromic NETs some gene mutations are associated with specific clinico-pathological features and prognosis. There have been several advances in our understanding of the NETs leading to earlier detection and targeted therapeutic treatment, but given the poor prognosis associated with metastatic NETs, it will be necessary to find new biomarkers for the prediction of malignant potential and to find novel therapeutic targets for NETs.

Liu IH, Ford JM, Kunz PL
DNA-repair defects in pancreatic neuroendocrine tumors and potential clinical applications.
Cancer Treat Rev. 2016; 44:1-9 [PubMed] Related Publications
BACKGROUND: The role of DNA repair in pathogenesis and response to treatment is not well understood in pancreatic neuroendocrine tumors (pNETs). However, the existing literature reveals important preliminary trends and targets in the genetic landscape of pNETs. Notably, pNETs have been shown to harbor defects in the direct reversal MGMT gene and the DNA mismatch repair genes, suggesting that these genes may be strong candidates for further prospective studies.
METHODS: PubMed searches were conducted for original studies assessing the DNA repair genes MGMT and MMR in pNETs, as well as for PTEN and MEN1, which are not directly DNA repair genes but are involved in DNA repair pathways. Searches were specific to pNETs, yielding five original studies on MGMT and four on MMR. Six original papers studied PTEN in pNETs. Five studied MEN1 in pNETs, and two others implicated MEN1 in DNA repair processes.
RESULTS: The five studies on MGMT in pNET tumor samples found MGMT loss of between 24% and 51% of tumor samples by IHC staining and between 0% and 40% by promoter hypermethylation, revealing discrepancies in methods assessing MGMT expression as well as potential weaknesses in the correlation between MGMT IHC expression and promoter hypermethylation rates. Four studies on MMR in pNET tumor samples indicated similar ambiguities, as promoter hypermethylation of the MLH1 MMR gene ranged from 0% to 31% of pNETs, while IHC staining revealed loss of MMR genes in between 0% and 36% of pNETs sampled. Studies also indicated that PTEN and MEN1 are commonly mutated or underexpressed genes in pNETs, although frequency of mutation or loss of expression was again variable among different studies.
CONCLUSION: Further studies are essential in determining a more thorough repertoire of DNA repair defects in pNETs and the clinical significance of these defects. This literature review synthesises the existing knowledge of relevant DNA repair pathways and studies of the specific genes that carry out these repair mechanisms in pNETs.

Zhou C, Zhang Y, Dai J, et al.
Pygo2 functions as a prognostic factor for glioma due to its up-regulation of H3K4me3 and promotion of MLL1/MLL2 complex recruitment.
Sci Rep. 2016; 6:22066 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Pygo2 has been discovered as an important Wnt signaling component contributing to the activation of Wnt-target gene transcription. In the present study, we discovered that Pygo2 mRNA and protein levels were up-regulated in the majority of (152/209) human brain glioma tissues and five glioma cell lines, and significantly correlated with the age, the WHO tumor classification and poor patient survival. The histone methyltransferase complex components (WDR5, Ash2, and menin, but not CXCC1 or NCOA6) were down-regulated at the promoter loci of Wnt target genes after Pygo2 knockdown, and this was accompanied by the down-regulation of Wnt/β-catenin pathway activity. Further, we demonstrated that the involvement of Pygo2 in the activation of the Wnt pathway in human glioma progression is through up-regulation of the H3K4me3 (but not H3K4me2) by promoting the recruitment of the histone methyltransferase MLL1/MLL2 complex to Wnt target gene promoters. Thus, our study provided evidence that Pygo2 functions as a novel prognostic marker and represents a potential therapeutic target.

Concolino P, Costella A, Capoluongo E
Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years.
Cancer Genet. 2016 Jan-Feb; 209(1-2):36-41 [PubMed] Related Publications
This review will focus on the germline MEN1 mutations that have been reported in patients with MEN1 and other hereditary endocrine disorders from 2007 to September 2015. A comprehensive review regarding the analysis of 1336 MEN1 mutations reported in the first decade following the gene's identification was performed by Lemos and Thakker in 2008. No other similar papers are available in literature apart from these data. We also checked for the list of Locus-Specific DataBases (LSDBs) and we found five MEN1 free-online mutational databases. 151 articles from the NCBI PubMed literature database were read and evaluated and a total of 75 MEN1 variants were found. On the contrary, 67, 22 and 44 novel MEN1 variants were obtained from ClinVar, MEN1 at Café Variome and HGMD (The Human Gene Mutation Database) databases respectively. A final careful analysis of MEN1 mutations affecting the coding region was performed.

Ishii J, Yazawa T, Chiba T, et al.
PROX1 Promotes Secretory Granule Formation in Medullary Thyroid Cancer Cells.
Endocrinology. 2016; 157(3):1289-98 [PubMed] Related Publications
Mechanisms of endocrine secretory granule (SG) formation in thyroid C cells and medullary thyroid cancer (MTC) cells have not been fully elucidated. Here we directly demonstrated that PROX1, a developmental homeobox gene, is transcriptionally involved in SG formation in MTC, which is derived from C cells. Analyses using gene expression databases on web sites revealed that, among thyroid cancer cells, MTC cells specifically and highly express PROX1 as well as several SG-forming molecule genes. Immunohistochemical analyses showed that in vivo MTC and C cells expressed PROX1, although follicular thyroid cancer and papillary thyroid cancer cells, normal follicular cells did not. Knockdown of PROX1 in an MTC cells reduced SGs detected by electron microscopy, and decreased expression of SG-related genes (chromogranin A, chromogranin B, secretogranin II, secretogranin III, synaptophysin, and carboxypeptidase E). Conversely, the introduction of a PROX1 transgene into a papillary thyroid cancer and anaplastic thyroid cancer cells induced the expression of SG-related genes. Reporter assays using the promoter sequence of chromogranin A showed that PROX1 activates the chromogranin A gene in addition to the known regulatory mechanisms, which are mediated via the cAMP response element binding protein and the repressor element 1-silencing transcription factor. Furthermore, chromatin immunoprecipitation-PCR assays demonstrated that PROX1 binds to the transcriptional regulatory element of the chromogranin A gene. In conclusion, PROX1 is an important regulator of endocrine SG formation in MTC cells.

Bhatti TR, Ganapathy K, Huppmann AR, et al.
Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect.
J Clin Endocrinol Metab. 2016; 101(3):914-22 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized.
OBJECTIVE: The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia.
RESULTS: Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11.
CONCLUSIONS: These data indicate that MEN1 mutations are more common in insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 and non-MEN1 insulinomas. The novel observation of a paternal parent-of-origin effect in all MEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of β-cell endocrine tumors in children.

van Leeuwaarde RS, van Nesselrooij BP, Hermus AR, et al.
Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group.
J Clin Endocrinol Metab. 2016; 101(3):1159-65 [PubMed] Related Publications
OBJECTIVE: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk.
DESIGN: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393).
RESULTS: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time.
CONCLUSION: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.

Perakakis N, Flohr F, Kayser G, et al.
Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype.
Hormones (Athens). 2016 Jan-Mar; 15(1):113-7 [PubMed] Related Publications
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant hereditary disorder associated with the development of endocrine tumors due to reduced expression of the tumor suppressor protein menin. Recent studies indicate a general role of menin in carcinogenesis, affecting the prevalence and clinical course of common non-endocrine tumors such as breast cancer, hepatocellular carcinoma and melanoma. Here we report a new germline missense mutation of Men1 in a German family with atypical tumor phenotype over three generations. Based on the type of mutation, we discuss possible changes in menin function leading to atypical tumorigenesis and present the clinical significance of such findings.
CASE PRESENTATION: A German family with a history of primary hyperparathyroidism presented to our Hospital for further evaluation. Members of the family demonstrated many different atypical tumors, such as renal cell carcinoma, papillary thyroid cancer and prostate cancer. DNA sequencing from peripheral blood revealed a novel mutation: Ser38Cys [TCC>TGC] in exon 2, codon 38 of Men1. This novel mutation is located in a region of menin which is responsible for interactions with the transcription factor JunD. This factor has recently been associated with prostate cancer. DNA sequencing of two of the atypical tumors (prostate cancer, papillary thyroid cancer) did not reveal a loss of heterozygosity, indicating an impact on menin expression and function in the heterozygous state, in line with results in +/-Men1 mutant mice developing prostate cancer.
CONCLUSION: The results and clinical course of disease in this case indicate the potential role of menin in the development of non-endocrine or atypical-endocrine tumors in MEN1 patients. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis. Nevertheless, in families with uncommon manifestations of the syndrome early diagnostic adjustments should be considered.

Neychev V, Sadowski SM, Zhu J, et al.
Neuroendocrine Tumor of the Pancreas as a Manifestation of Cowden Syndrome: A Case Report.
J Clin Endocrinol Metab. 2016; 101(2):353-8 [PubMed] Related Publications
CONTEXT: Germline mutations in the phosphatase and tensin homolog (PTEN) tumor suppressor gene are found in the majority of patients with Cowden syndrome (CS), who have an increased risk of breast, thyroid, and endometrial cancer. According to our current understanding of genetic changes in the PTEN gene and the resultant phenotypic features of CS, pancreatic neuroendocrine tumors (NETs) are not considered part of the clinical spectrum of CS.
CASE DESCRIPTION: We report a unique case of an advanced NET of the pancreas in a patient with CS. The germline DNA sequencing confirmed the clinical diagnosis of CS and revealed a PTEN mutation c.697C→T (p.R233*) causing a premature stop codon in exon 7. The tumor DNA sequencing showed no loss of heterozygosity or any copy number changes and no other deleterious genetic alterations, including those commonly mutated in sporadic pancreatic NETs: MEN1, ATRX, DAXX, TP53, and genes involved in the mammalian target of rapamycin pathway. In addition, the high-throughput transcriptome analyzed by RNA-seq did not reveal any missed genetic alterations, aberrant splicing variants, gene fusions, or gene expression alterations. The immunohistochemical staining of the tumor for PTEN revealed an abnormal, uniformly strong cytoplasmic staining of tumor cells with virtually absent nuclear staining.
CONCLUSION: The results from genetic testing and histopathological techniques used to confirm CS diagnosis and characterize this unusual tumor tempted us to believe that in this case, the pancreatic NET was not a sporadic malignancy that occurred by coincidence, but rather represented a new entity in the spectrum of malignancies associated with CS.

Rostomyan L, Daly AF, Beckers A
Pituitary gigantism: Causes and clinical characteristics.
Ann Endocrinol (Paris). 2015; 76(6):643-9 [PubMed] Related Publications
Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome.

Fujiya A, Kato M, Shibata T, Sobajima H
VIPoma with multiple endocrine neoplasia type 1 identified as an atypical gene mutation.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
A 47-year-old man presented with persistent diarrhoea and hypokalaemia. CT revealed 4 pancreatic tumours that appeared to be VIPomas, because the patient had an elevated plasma vasoactive intestinal polypeptide level. MRI showed a low-intensity area in the pituitary suggestive of a pituitary tumour, and a parathyroid tumour was detected by ultrasonography and 99Tc-MIBI scintigraphy. Given these results, the patient was diagnosed with multiple endocrine neoplasia type 1 (MEN1) and scheduled for surgery. MEN1 is an autosomal dominant disorder associated with MEN1 mutations. Genetic testing indicated that the patient had a MEN1 gene mutation; his 2 sons had the same mutations. Most MEN1 tumours are benign, but some pancreatic and thymic tumours could become malignant. Without treatment, such tumours would result in earlier mortality. Despite its rarity, we should perform genetic testing for family members of patients with MEN1 to identify mutation carriers and improve the patients' prognosis.

Fyrsten E, Norlén O, Hessman O, et al.
Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism?
World J Surg. 2016; 40(3):615-21 [PubMed] Related Publications
BACKGROUND: Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) is surgically treated with either a subtotal parathyroidectomy removing 3 or 3,5 glands (SPX), less than 3 glands (LSPX), or a total parathyroidectomy with autotransplantation (TPX). Previous studies with shorter follow-up have shown that LSPX and SPX are associated with recurrent HPT, and TPX with hypocalcemia and substitution therapy. We examined the situation after long-term follow-up (median 20,6 years).
METHODS: Sixty-nine patients with MEN1 HPT underwent 110 operations, the first operation being 31 LSPX, 30 SPX, and 8 TPX. Thirty patients underwent reoperative surgery in median 120 months later, as completion to TPX (n = 12), completion of LSPX to SPX (n = 9), extirpation of single glands (n = 3) still resulting in LSPX, and resection of forearm grafts (n = 3). Nine patients underwent a second, and 2 a third reoperation. In 24 patients genetic testing confirmed MEN1, and in the remaining heredity and phenotype led to the diagnosis.
RESULTS: TPX had higher risk for hypoparathyroidism necessitating substitution therapy, at latest follow-up 50%, compared to SPX (16% after 3-6 months; none at latest follow-up). Recurrent HPT was common after LSPX, leading to 24 reoperations in 17 patients. No need for substitution therapy after SPX indicated forthcoming recurrent disease. Not having hypocalcemia in the postoperative period and less radical surgery than TPX were significantly associated to risk for recurrence. Further, mutation in exon 3 in the MEN1 gene may eventually be linked to risk of recurrence.
CONCLUSION: LSPX is highly associated with recurrence and TPX with continuous hypoparathyroidism, also after long-term follow-up. SPX should be the chosen method in the majority of patients with MEN1 HPT.

Yu Y, Dong L, Li D, et al.
Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer.
Sci Rep. 2015; 5:16129 [PubMed] Free Access to Full Article Related Publications
Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500× coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients.

Barbu A, Lejonklou MH, Skogseid B
Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model.
Pancreas. 2016; 45(4):533-40 [PubMed] Related Publications
OBJECTIVES: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1(+/−) mice.
METHODS: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis.
RESULTS: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade.
CONCLUSIONS: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.

Alevizaki M, Saltiki K
Primary Hyperparathyroidism in MEN2 Syndromes.
Recent Results Cancer Res. 2015; 204:179-86 [PubMed] Related Publications
One of the components of trethe classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. The prevalence is more rare in gene carriers as these frequently have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, codon 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis after the 3rd decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation.

Yang GC
Cytohistology of papillary carcinoid and emerging concept of pulmonary neuroendocrine neoplasms.
Diagn Cytopathol. 2016; 44(1):52-60 [PubMed] Related Publications
This timely review starts by reporting the clinical, cytologic and histologic features of a morphologic variant of pulmonary carcinoid tumor forming exclusively of papillae. This growth pattern is so rare that it was not included in 2014 WHO classification of pulmonary neuroendocrine neoplasms. The current concept is reviewed, and example of spindle cell carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma are illustrated with fine needle aspiration cytology, surgical and clinical follow-up. Finally, the new findings in cell biology and molecular biology that led to the emerging concept that carcinoids and high-grade neuroendocrine lung carcinomas are separate biological entities are reviewed and summarized in a tumorigenic module.

Cheng P, Wang YF, Li G, et al.
Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway.
Cancer Lett. 2016; 370(1):136-44 [PubMed] Related Publications
Menin, the product of the Men1 gene, which is frequently mutated in pancreatic neuroendocrine tumors, acts as a chromatin-remodeling factor to modulate the transcription of cell cycle regulators by interacting with histone modification factors. However, the function of menin and its underlying mechanisms in pancreatic ductal adenocarcinoma remain unknown. Here, we found that menin inhibited pancreatic cancer cell growth in vitro and in vivo and that its expression was gradually lost during pancreatic carcinogenesis. Menin overexpression significantly activated the expression of the cyclin-dependent kinase (CDK) inhibitors p18 and p27, accompanied with a decrease in DNA methylation levels of p18 and p27 promoters. Mechanistically, we found that interaction of menin with DNA methyltransferase 1 (Dnmt1) competitively pulled down Dnmt1 from p18 and p27 promoters, leading to the downregulation of DNA methylation levels. Moreover, menin expression was suppressed by Dnmt1 downstream of the Hedgehog signaling pathway, and menin overexpression strongly antagonized the promotion effect of hedgehog signaling on pancreatic cancer cell proliferation. Taken together, the interaction between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of Hedgehog pathways with complex mutual modulation networks, suggesting that the Hedgehog/Dnmt1/menin axis is a potential molecular target for pancreatic cancer therapy.

Murakami T, Usui T, Nakajima A, et al.
A Novel Missense Mutation of the MEN1 Gene in a Patient with Multiple Endocrine Neoplasia Type 1 with Glucagonoma and Obesity.
Intern Med. 2015; 54(19):2475-81 [PubMed] Related Publications
A 35-year-old obese diabetic man presented with recurrent primary hyperparathyroidism during a three-year outpatient follow-up. He was clinically diagnosed with multiple endocrine neoplasia type 1 (MEN1) due to the presence of a pituitary adenoma and multiple glucagonomas. The glucagonomas may have affected his glycemic control. However, he did not demonstrate weight loss, suggesting that the patient's obesity could have obscured the early diagnosis of a glucagonoma. Genetic testing revealed a novel missense mutation at codon 561 in exon 10, resulting in an amino acid substitution from methionine to arginine (M561R) in the MEN1 gene. This mutation appeared to be responsible for the MEN1 pathogenicity.

Thevenon J, Bourredjem A, Faivre L, et al.
Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.
Eur J Endocrinol. 2015; 173(6):819-26 [PubMed] Related Publications
BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.
METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.
RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.
CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Norton JA, Krampitz G, Jensen RT
Multiple Endocrine Neoplasia: Genetics and Clinical Management.
Surg Oncol Clin N Am. 2015; 24(4):795-832 [PubMed] Free Access to Full Article Related Publications
Early diagnosis of multiple endocrine neoplasia (MEN) syndromes is critical for optimal clinical outcomes; before the MEN syndromes can be diagnosed, they must be suspected. Genetic testing for germline alterations in both the MEN type 1 (MEN1) gene and RET proto-oncogene is crucial to identifying those at risk in affected kindreds and directing timely surveillance and surgical therapy to those at greatest risk of potentially life-threatening neoplasia. Pancreatic, thymic, and bronchial neuroendocrine tumors are the leading cause of death in patients with MEN1 and should be aggressively considered by at least biannual computed tomography imaging.

Lines KE, Stevenson M, Thakker RV
Animal models of pituitary neoplasia.
Mol Cell Endocrinol. 2016; 421:68-81 [PubMed] Free Access to Full Article Related Publications
Pituitary neoplasias can occur as part of a complex inherited disorder, or more commonly as sporadic (non-familial) disease. Studies of the molecular and genetic mechanisms causing such pituitary tumours have identified dysregulation of >35 genes, with many revealed by studies in mice, rats and zebrafish. Strategies used to generate these animal models have included gene knockout, gene knockin and transgenic over-expression, as well as chemical mutagenesis and drug induction. These animal models provide an important resource for investigation of tissue-specific tumourigenic mechanisms, and evaluations of novel therapies, illustrated by studies into multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome in which ∼ 30% of patients develop pituitary adenomas. This review describes animal models of pituitary neoplasia that have been generated, together with some recent advances in gene editing technologies, and an illustration of the use of the Men1 mouse as a pre clinical model for evaluating novel therapies.

Jyotsna VP, Malik E, Birla S, Sharma A
Novel MEN 1 gene findings in rare sporadic insulinoma--a case control study.
BMC Endocr Disord. 2015; 15:44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Insulinomas, which are rare tumors causing hyperinsulinemic hypoglycemia are usually sporadic but may also occur in association with multiple endocrine neoplasia type 1 (MEN-1) syndrome an autosomal dominant disorder caused by MEN1 gene mutations. MEN1 encodes a nuclear protein Menin, a tumor suppressor which acts as an adapter and interacts with partner proteins involved in crucial activities like transcriptional regulation, cell division, proliferation and genome stability. This study reports on clinical findings and mutation screening in sporadic insulinoma patients.
METHODS: Seventeen patients diagnosed with insulinoma were recruited along with 30 healthy volunteers who acted as controls for the present study. The patients presented with symptoms of sweating, tremors, drowsiness, palpitations, loss of consciousness, abnormal behavior, seizures and weight gain. Detailed clinical and family history was collected from all the participants along with 5 ml of blood sample after taking informed consent. Genomic DNA isolated from blood was subjected to MEN1 gene amplification followed by direct sequencing. Nucleotide sequences obtained were compared with published MEN1 cDNA sequences. Prediction of functional effects of novel changes was done using various bioinformatics algorithms.
RESULTS: Molecular analysis revealed presence of three novel exonic mutations (M561K, Q192K and Q261Q), two novel intronic variations c.445-44G → A and c.913-42G → C in introns two and six respectively and three reported exon SNPs; H433H (rs540012), D418D (rs2071313), A541T (rs2959656) and one intronic SNP (rs669976).
CONCLUSIONS: The study identified presence of novel pathogenic MEN1 mutations in sporadic cases of insulinoma. The new mutations identified were in regions involved in defective binding of menin to proteins implicated in genetic and epigenetic mechanisms. The outcome of the study extends the growing list of MEN1 pathogenic mutations even in sporadic cases providing consequential insight into phenotypic heterogeneity and in the expression of individual mutations.

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