Materiały źródłowe

• #1 Multiple Endocrine Neoplasia Type 1 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536980/

  Multiple endocrine neoplasia type 1 (MEN1) is a rare endocrine tumor syndrome with high penetrance. This syndrome is also known as Wermer syndrome. It primarily causes neoplasia of the parathyroid glands, the anterior pituitary gland, and the neuroendocrine tissue of gastro-entero-pancreatic organ systems. Hyperparathyroidism is the most common manifestation and occurs in 90% of cases. Similarly, pancreatic neuroendocrine tumors occur in 60% of cases, while pituitary adenomas occur in 40% of cases. The affected patient, however, may also develop less common endocrine and non-endocrine tumors such as carcinoid tumors of the thymus, bronchus, or stomach, adrenocortical tumors, cutaneous tumors, central nervous system (CNS) tumors, leiomyomas, lipomas, collagenomas, and angiofibromas. […] MEN1 gene testing in an index case can confirm the diagnosis and allow early detection of asymptomatic mutation carriers years before a MEN1-associated tumor can be detected. However, approximately 20% of MEN1 kindred have no mutation in the MEN1 gene. Unfortunately, there is no genotypic-phenotypic correlation in MEN1, leading to different manifestations even among family members. Studies have demonstrated that nonsense and splicing mutations are associated with more aggressive neuroendocrine tumors.

• #1 Multiple endocrine neoplasia type 1 | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-38

  Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. […] The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. […] The mutated MEN1 allele is a germline mutation present in all cells at birth. The second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele; it gives cells the survival advantage needed for tumour development.

• #1 A narrative review of multiple endocrine neoplasia syndromes: genetics, clinical features, imaging findings, and diagnosis

  https://atm.amegroups.org/article/view/70303/html

  The MEN syndromes are a group of autosomal dominant genetic disorders with high penetrance. […] MEN1 is related to the inactivating mutation of the tumor suppressor gene MEN1 on chromosome 11. […] The pathogenesis of MEN1 is Knudsons 2-hit hypothesis. […] The mutation sites of the MEN1 gene are located in and around the open reading frame, and more than 1,300 mutation sites have been discovered. […] Although MEN1 mutations are mostly hereditary, 10% of MEN1 cases have a de novo germline. […] In 20-30% of MEN1 patients, germline mutations were not detected in the coding region of MEN1, which may be caused by gene deletions, noncoding region mutations, or other gene mutations. […] A study has shown that MEN1 promoter methylation may be associated with the severity of disease. […] Genetic testing is very important for the early diagnosis and identification of asymptomatic carriers.

• #1 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication | Test Fact Sheet

  https://arupconsult.com/ati/multiple-endocrine-neoplasia-type-1

  Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome caused by pathogenic variants in the MEN1 gene and is associated with a combination of endocrine and nonendocrine tumors. […] MEN1 is caused by pathogenic germline variants in the MEN1 tumor suppressor gene. Approximately 10% of these variants are de novo variants. […] The penetrance for all clinical features of MEN1 syndrome is approximately 50% by 20 years of age and is 95% by 40 years of age. […] A pathogenic MEN1 variant is identified in 80-90% of individuals who meet clinical criteria for MEN1 syndrome and have a family history of related cancers. Approximately 4% of pathogenic variants are large deletions or duplications. […] The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications. […] A negative result does not exclude a diagnosis of MEN1.

• #1 MEN1 – Wikipedia

  https://en.wikipedia.org/wiki/MEN1

  Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 (MEN-1 syndrome) and has autosomal dominant inheritance. Variations in the MEN1 gene can cause pituitary adenomas, hyperparathyroidism, pancreatic neuroendocrine tumors, gastrinoma, and adrenocortical cancers. […] Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin resulting in the inability of MEN1 to act as a tumor suppressor gene. Such mutations in MEN1 have been associated with defective binding of encoded menin to proteins implicated in genetic and epigenetic mechanisms. […] MEN1 mutations comprise mostly frameshift deletions or insertions, followed by nonsense, missense, splice-site mutations and either part or complete gene deletions resulting in disease pathology.

• #1 Multiple endocrine neoplasia type 1 (MEN1): Not only inherited endocrine tumors | Genetics in Medicine

  https://www.nature.com/articles/gim2009126

  MEN 1 is a rare hereditary cancer syndrome which manifests a variety of endocrine and non-endocrine neoplasms and lesions. […] The MEN1 gene is a tumor suppressor gene, and mutations in it account for the development of the MEN1 clinical syndrome through impairment of several cell functions, such as cell proliferations, cell growth control, apoptosis, DNA replication and repair, gene expression, transcriptional machinery control, and hormone secretion. […] The proposed model for tumorigenesis in familial MEN1 is, according to Knudson’s two hits hypothesis, a mutated MEN1 copy is inherited at the germline level from the affected parent (first hit), whereas the wild-type copy, inherited from the healthy parent, is lost at the somatic level (second hit), resulting in a tumor. […] These findings strongly suggested gene inactivation as the mechanism of tumorigenesis for MEN1.

• #1 Multiple endocrine neoplasia type 1 – Wikipedia

  https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1

  Multiple endocrine neoplasia type 1 (MEN-1 aka Wermer Syndrome) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. […] People with multiple endocrine neoplasia type 1 are born with one mutated copy of the MEN1 gene in each cell. Then, during their lifetime, the other copy of the gene is mutated in a small number of cells. These genetic changes result in no functional copies of the MEN1 gene in selected cells, allowing the cells to divide with little control and form tumors. This is known as Knudson’s two-hit hypothesis and is a common feature seen with inherited defects in tumor suppressor genes. […] The exact function of MEN1 and the protein, menin, produced by this gene is not known, but following the inheritance rules of the „two-hit hypothesis” indicates that it acts as a tumor suppressor.

• #1 Multiple endocrine neoplasia type 1 pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Multiple_endocrine_neoplasia_type_1_pathophysiology

  Multiple endocrine neoplasia type 1 is an autosomal dominant syndrome that is usually caused by mutations of the MEN1 gene. The pathophysiology of multiple endocrine neoplasia type 1 depends on the histological subtype. Multiple endocrine neoplasia involves tumors in at least two endocrine glands, and tumors can also develop in other organs and tissues. These tumors may be either benign or malignant. MEN type I is an autosomal dominant syndrome characterized by the development of the following tumors: Pituitary adenomas, Islet cell tumors of the pancreas (commonly gastrinoma and glucagonoma), Parathyroid hyperplasia with resulting hyperparathyroidism. […] MEN1 gene is a putative tumor suppressor gene and causes multiple endocrine neoplasia type 1 by Knudson’s „two hits” model for tumor development.

• #1 Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature

  https://www.spandidos-publications.com/10.3892/ol.2014.2144

  Multiple endocrine neoplasia type 1 (MEN1) is a cancer predisposition syndrome that includes a combination of endocrine and nonendocrine tumors. […] The MEN1 gene is located on chromosome 11q13. […] Previous studies of loss of heterozygosity (LOH) by microsatellite analysis in tumor tissues of MEN1 patients have supported a tumor suppressor function of the MEN1 gene. […] The MEN1 gene responsible for MEN1 acts as a tumor suppressor gene, and tumors in MEN1 arise through the two-hit mechanism. The first hit is a germline mutation, and the second hit is a somatic inactivation of the remaining wild-type allele in a single cell of certain tissues, which initiates neoplastic transformation. […] The product of the MEN1 gene, menin, is a nuclear protein whose interaction with several nuclear proteins indicates a role in transcriptional regulation.

• #1 Multiple endocrine neoplasia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/multiple-endocrine-neoplasia/

  Mutations in the MEN1 gene cause multiple endocrine neoplasia type 1. This gene provides instructions for producing a protein called menin. Menin acts as a tumor suppressor, which means it normally keeps cells from growing and dividing too rapidly or in an uncontrolled way. Although the exact function of menin is unknown, it is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. When mutations inactivate both copies of the MEN1 gene, menin is no longer available to control cell growth and division. The loss of functional menin allows cells to divide too frequently, leading to the formation of tumors characteristic of multiple endocrine neoplasia type 1. It is unclear why these tumors preferentially affect endocrine tissues. […] Mutations in the RET gene cause multiple endocrine neoplasia type 2. This gene provides instructions for producing a protein that is involved in signaling within cells. The RET protein triggers chemical reactions that instruct cells to respond to their environment, for example by dividing or maturing. Mutations in the RET gene overactivate the protein’s signaling function, which can trigger cell growth and division in the absence of signals from outside the cell. This unchecked cell division can lead to the formation of tumors in endocrine glands and other tissues.

• #1 Multiple endocrine neoplasia type 1 — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/multiple-endocrine-neoplasia-type-1/

  Multiple endocrine neoplasia type 1 is a condition associated with variants in the MEN1 gene that causes predisposition to tumours in the endocrine organs. […] MEN1 is caused by constitutional (germline) pathogenic loss-of-function variants in the MEN1 tumour suppressor gene, which codes for the menin protein. […] Menin can interact with many other proteins and is thought to regulate gene transcription via chromatin remodelling. […] The majority of pathogenic MEN1 variants result in a truncated protein. […] It can be caused by de novo variants in MEN1 (around 10% of cases) and, rarely, it can take a mosaic form.

• #1 MEN1 (multiple endocrine neoplasia I)

  https://atlasgeneticsoncology.org/gene/148/men1-(multiple-endocrine-neoplasia-i)

  the MEN1 gene is a growth-suppressor gene, as shown by allelic deletion (LOH) in tumoral DNA from MEN1 patients; menin has been showed to interact with the AP1 transcrition factor through his JunD component; this interaction involves mainly the first 40 amino-acids at the N-terminal end of menin and some specifics amino-acids in the central domain of the protein; Menin interacts specifically with JunD but with none of the other AP1 proteins, such as JunB, c-Jun, c-Fos and Fra1/2; among 11 missense mutations described in MEN1 patients, the authors reported that four of them decreased or abolished binding to JunD suggesting a separate domain between amino-acids residues 139 and 142 could have a critical role in menin-JunD interaction; using mammalian two-hybrid assays, menin has been shown to repress JunD-mediated transcriptionnal activation but most of menin mutatnts with impaired JunD-binding properties lossed this inhibitory activity; strikingly, overexpression of normal or mutant menin in similar experimental assays led to the absence of repressional activity suggesting that unknown factors could be involved in the menin-JunD interaction; new partners binding menin will be probably characterized in a near future and help us to understand the MEN1-related pathways

• #1 MEN1 Latest Insights | Endocrine Society

  https://www.endocrine.org/journals/endocrine-reviews/men1-latest-insights

  Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. […] The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor /bone morphogenetic protein, a few nuclear receptors, Wnt/-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions.

• #1 Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype–phenotype correlation | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-variable-clinical-expression-in-patients-S1807593222023961

  Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. […] Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotypephenotype correlation has been established.

• #1 Multiple Endocrine Neoplasia, Type 1 (MEN 1) – Endocrine and Metabolic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/multiple-endocrine-neoplasia-men-syndromes/multiple-endocrine-neoplasia-type-1-men-1

  Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors), and/or pituitary gland tumors. […] MEN 1 is caused by an inactivating mutation of the MEN1 gene that encodes the nuclear protein menin; 500 mutations of this gene have been identified. The exact function of menin is unknown, but it appears to have tumor-suppressing effects. […] Some mutations are thought to be associated with a higher rate of pancreatic islet cell tumor development, a higher rate of distant metastases, and more aggressive disease.

• #1

  https://journals.lww.com/md-journal/fulltext/2021/12100/a_case_report_of_multiple_endocrine_neoplasia_type.61.aspx

  Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is challenging, as MEN1 affects different endocrine tissues and predisposes to both benign and malignant tumors. MENIN-deficient cells have recently been recognized to play a role in triggering autoimmunity. […] With the present case, the authors highlight a new interplay between MENIN and the immune system, which may have implications for future targeted life-long surveillance and treatment of MEN1 patients. […] Although the loss of MENIN expression is a sine qua non condition for the development of MEN1-associated tumors, in silico functional analysis showed that variants in genes involved in the same proliferative and apoptotic tumorigenic pathways may act as modifiers, including Kirsten rat sarcoma virus (KRAS), Wnt Family Member 2B (WNT2B), Interleukin 3 Receptor Subunit Alpha (IL3RA) and TNF Receptor Superfamily Member 10A (TNFRSF10A).

• #1 A New Medical Therapy for Multiple Endocrine Neoplasia Type 1? – touchENDOCRINOLOGY

  https://touchendocrinology.com/endocrine-oncology/journal-articles/a-new-medical-therapy-for-multiple-endocrine-neoplasia-type-1/

  Pancreatic neuroendocrine tumours (pNETs) are a major manifestation of multiple endocrine neoplasia type 1 (MEN1), and the most significant cause of morbidity and mortality in this disorder. […] A recent study has shown that in cell line and animal models, MEN1 mutations lead to an upregulation of the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in increasing precursor metabolites for the synthesis of pyrimidines. […] The MEN1 syndrome is caused by germ-line heterozygote inactivating mutations of the MEN1 gene, which encodes menin, a tumour suppressor protein. MEN1-related pNETs develop following the complete loss of function of wild-type menin due to loss of heterozygosity, according to the Knudson two-hit hypothesis. Menin is a key regulator of endocrine cell plasticity, and its loss in these cells is sufficient for tumour initiation.

• #1 Article – Journal Bone Fragility

  https://www.journalbonefragility.com/article/2024/4/3/108/the-involvement-of-micrornas-in-multiple-endocrine-neoplasia-type-1/

  Multiple endocrine neoplasia type 1 (MEN1) syndrome is caused by mutations in the MEN1 gene, resulting in reduced or completely absent production of the oncosuppressor menin. This genotype often results in the occurrence of tumors in endocrine tissues (parathyroids, pituitary gland, and endocrine pancreas) and beyond. […] Over the past 20 years, it has been seen that deregulation of microRNA (miRNA) expression may play a key role in the onset and progression of several diseases, including MEN1. […] In this review, we look at the miRNAs that might be involved in the pathogenesis of MEN1, and therefore represent possible targets for developing new therapies for the syndrome. In addition, we discuss the possibility of using some circulating miRNAs as potential future diagnostic and prognostic biomarkers of MEN1.

• #1

  https://figshare.utas.edu.au/articles/thesis/The_pathogenesis_and_behaviour_of_clinical_endocrinopathy_in_multiple_endocrine_neoplasia_type_1/23236010

  As a first year medical student at the University of Tasmania in 1984, I learned of the rare autosomal dominant disease – multiple endocrine neoplasia type 1 (MEN 1), then newly recognised to be at high prevalence in the island state of Tasmania. MEN 1 had been reported to be an „all or none” syndrome characterised by the triad of parathyroid hyperplasia pancreatic neoplasia and pituitary tumour. […] The research presented in this thesis was undertaken by myself between 1995 and 1998 in an attempt to establish the extent and aetiology of phenotypic variability in MEN 1 disease expression. […] 2. To determine if a role exists for heritable disease modifier factor(s) in the pathogenesis of disease associated with MEN 1. […] Whilst a mutation of the MEN 1 gene is central to the pathogenesis of disease in MEN 1 disease modifier factors have an important role in determining the development and clinical behaviour of MEN 1 disease phenotypes.

• #2 Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome – Cancer Syndromes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7029/

  Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30-80% of cases), and anterior pituitary (15-90% of cases) (Figure 1) (1). […] MEN1 gene mutations can be identified in 70-95% of MEN1 patients. […] MEN1 follows Knudsons two-hit model for tumor suppressor gene carcinogenesis (30). The first hit is a heterozygous MEN1 germline mutation, inherited from one parent (familial cases) or developed in an early embryonic stage (sporadic cases) and present in all cells at birth. The second hit is a MEN1 somatic mutation, usually a large deletion, that occurs in the predisposed endocrine cell as loss of the remaining wild-type allele and gives cells the survival advantage needed for tumor development (31).

• #2 MEN1 (multiple endocrine neoplasia I)

  https://atlasgeneticsoncology.org/gene/148/men1-(multiple-endocrine-neoplasia-i)

  germline mutations in the MEN1 gene cause familial and sporadic multiple endocrine neoplasia type 1 (MEN1) and the majority of mutations described predict premature protein truncation either by nonsenses and frameshifts in coding sequences; missense mutations have been identified in 30% of cases and when characterized in sporadic cases, most of them need analysis of a large ( 50) number of control individuals in order to exclude frequent polymorphisms; interestingly, all truncating mutations affect one or both NLSs and no missense mutations were observed inside NLS-1 and NLS-2; mutations are spread over the gene and most of them occur once in a single family; some mutations were observed in more than one family and when a common ancestor was excluded by haplotyping, these recurrent mutations might be accounted for hot-spots in the MEN1 sequence; most recurrent mutations are nonsenses and frameshifts in exons 2 and 10; for example, single base deletion occurs frequently at nucleotide 1650 in exon 10 and has been related to the presence of an highly repetitive motif (CCCCCCCG) in this region inducing replication errors by slipped-strand mispairing; between 10 and 15% of sporadic MEN1 could be explained by de novo mutations, but this must be confirmed by an exhautive analysis of affected individuals and both parents

• #2 Multiple endocrine neoplasia type 1 pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Multiple_endocrine_neoplasia_type_1_pathophysiology

  Knudson’s „two hits” model for tumor development suggest that there is a germline mutation present in all cells at birth and the second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele. This „two hits” model gives cells the survival advantage needed for tumor development.

• #2

  https://omim.org/entry/131100

  The observation of LOH involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit’ model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. […] Pannett and Thakker (2001) searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit’ hypothesis.

• #2 Multiple endocrine neoplasia type 1 | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-38

  The nuclear localisation of menin suggests that this protein may have an important role in the regulation of DNA transcription and replication, in cell cycle, or in the maintenance of genome integrity. […] There is increasing evidence that menin may act in DNA repair or synthesis, but the exact mechanism by which menin regulates DNA synthesis or DNA repair in response to DNA damage, is currently unknown.

• #2 Multiple endocrine neoplasia type 1 (MEN1): Not only inherited endocrine tumors | Genetics in Medicine

  https://www.nature.com/articles/gim2009126

  Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. […] Menin may inhibit JunD-mediated transcriptional activation, because studies of deletion mutants have shown the existence of interacting regions of both proteins. […] Menin could inhibit JunD-mediated transcription by modification of chromatin structure recruiting a specific histone deacetylase targeted to a promoter by binding JunD. […] Menin has been reported to interact with a multitude of proteins, other than JunD, including SMAD family members, Pem, NFB, FANCD2, RPA2, NMMHC II-A, GFAP, vimentin, p53, and Hsp70, although to date none of the interacting partners have been directly proved important in MEN1 pathophysiology. […] It has been hypothesized that menin may mediate its tumor suppressor action by regulating histone methylation in promoters of HOX genes and/or CDKN2C/p18, CDKN1B/p27, and possibly other CDKIs.

• #2 Frontiers | Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00339/full

  MEN1 acts as a tumor suppressor gene. […] Neoplasms develop (as described in Knudson’s two-hit hypothesis), when a second somatic inactivating mutation occurs in one MEN1 allele in the setting of the preexisting germline inactivating mutation in the alternate allele. […] The protein product of MEN1, menin, is implicated in the regulation of transcription, genome stability, cell division, and cell proliferation, though the exact role of menin in tumorigenesis is yet to be elucidated. […] Mutations in MEN1 that lead to premature protein truncation may lead to functional inactivation of menin through loss of one or both main NLSs. […] Menin is predicted to be a multi-functional protein that plays a role in epigenetic regulation and gene transcription through interaction with proteins in chromatin-associated protein complexes and transcription factors, with regulation of gene expression of target genes such as those that control cell proliferation. […] In genetically engineered mouse models, germline targeted deletion of both copies of the Men1 gene leads to death in utero, whereas germline targeted deletion of one copy of the Men1 gene results in live mice that develop endocrine tumors similar to those in humans.

• #2 Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome – Cancer Syndromes – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7029/

  More than two-thirds of all identified mutations (frameshifts, nonsense, and some splicing site mutations) predict a loss-of-function of menin, and therefore support the hypothesis that MEN1 is a tumor suppressor gene. Other splicing site mutations can lead to retention of incompletely spliced precursors, complete absence of transcripts, or appearance of aberrantly processed mRNAs from the creation of novel or cryptic splicing sites or from the loss of classical splicing sites. […] The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression.

• #2 Multiple endocrine neoplasia type 1 with a frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas: case report | BMC Endocrine Disorders | Full Text

  https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-021-00821-7

  Such mutation inactivates MEN1 tumor suppressor gene, which is involved in the regulation of DNA replication and repair. […] Germline inactivating mutations in the MEN1 gene that encodes menin predispose subjects to develop fatty change and/or tumors in various endocrine organs such as the pancreas and parathyroid. […] Inactivation of menin in various MEN1-associated endocrine tissues facilitates epigenetic changes which finally leads to fatty change and tumorigenesis. […] While it was known that MEN1 gene product menin interacted with another important molecule checkpoint kinase 1 (Ches1), it was reported that some mutation in exon 10 of MEN1 gene disturbed the interaction between Menin and Ches1 and thereby augmented the possibility of endocrine tumor in the pancreas. […] This case also had a frameshift mutation in exon 10 of MEN1 gene. […] Therefore, although speculative, we assume that the abnormality in the pancreas was associated with a frameshift mutation in exon 10 in this subject.

• #2 Multiple Endocrine Neoplasia Type 1 – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536980/

  Germline inactivating mutations of the MEN1 or menin gene on chromosome 11 results in MEN1 Syndrome. MEN1 syndrome is inherited in an autosomal dominant pattern. In approximately 90% of cases, mutations are inherited from an affected parent, while in the remaining 10% of cases, the syndrome occurs secondary to a de novo mutation. Given this latter figure, clinical diagnostic criteria remain of utmost importance in diagnosing this syndrome. […] Marini et al. published an analysis of germline MEN1 mutations in 410 patients and found 99 different mutations, 41 frameshift, 26 missense, 13 nonsense, 11 splicing site mutations, 4 in-frame small deletions, and 4 large intragenic deletions spanning over 1 exon. The study also demonstrated that gastro-entero-pancreatic tumors were more common in patients with nonsense mutations, while thoracic neuroendocrine tumors were more common in individuals bearing a splice mutation. Germline mutations of CDKN1B have also been associated with pituitary adenomas, parathyroid adenomas, and pancreatic neuroendocrine tumors. Therefore, it is possible that mutations in this gene could potentially account for MEN1 syndromes without MEN1 gene mutation.

• #2 Multiple endocrine neoplasia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/multiple-endocrine-neoplasia/

  Mutations in the CDKN1B gene cause multiple endocrine neoplasia type 4. This gene provides instructions for making a protein called p27. Like the menin protein, p27 is a tumor suppressor that helps control the growth and division of cells. Mutations in the CDKN1B gene reduce the amount of functional p27, which allows cells to grow and divide unchecked. This unregulated cell division can lead to the development of tumors in endocrine glands and other tissues.

• #2 Multiple Endocrine Neoplasia (MEN) Syndromes | UCSF Department of Surgery

  https://surgicaloncology.ucsf.edu/condition/multiple-endocrine-neoplasia-men-syndromes

  Mutations in the CDKN1B gene cause multiple endocrine neoplasia type 4. This gene provides instructions for making a protein called p27. Like the menin protein, p27 is a tumor suppressor that helps control the growth and division of cells. Mutations in the CDKN1B gene reduce the amount of functional p27, which allows cells to grow and divide unchecked. This unregulated cell division can lead to the development of tumors in endocrine glands and other tissues.

• #2 A narrative review of multiple endocrine neoplasia syndromes: genetics, clinical features, imaging findings, and diagnosis

  https://atm.amegroups.org/article/view/70303/html

  The proto-oncogene RET, with 21 exons, is located on chromosome 10q11.2 and encodes a membrane-bound tyrosine kinase cell surface receptor. […] Mutations of the RET gene are present in 98% of MEN2 patients. […] Significant genotype-phenotype correlations have been detected in MEN2 patients. […] Genetic testing of RET can confirm the diagnosis and predict the potential phenotype, which can guide clinical management. […] The tumor suppressor gene CDKN1B, located at 12q13, encodes nuclear protein p27, which is a CDK inhibitor that can regulate the transition of cells from G1 phase to S phase. […] Approximately 3% of patients clinically diagnosed with MEN1 do not have MEN1 mutations but carry CDKN1B mutations. […] The clinical manifestations of MEN4 are similar to those of MEN1. […] According to the reported cases, some phenotypic characteristics of MEN4 have been summarized.

• #2 Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype–phenotype correlation | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-variable-clinical-expression-in-patients-S1807593222023961

  In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotypephenotype correlation. […] It appears that in the MEN1 syndrome, clinical expression differs between families. This may be the result of the specific MEN1 gene mutation in a family (genotypephenotype correlation). As a rule, the development of a tumor depends on a series of genetic events (multistep tumorigenesis). Thus, additional co-segregating modifying factors such as germline mutations in other genes are likely to play a role in the interfamilial variability of MEN 1. Moreover, clinical expression can also vary between individual members of the same family, possibly because of additional genetic or epigenetic factors.

• #2 A New Medical Therapy for Multiple Endocrine Neoplasia Type 1? – touchENDOCRINOLOGY

  https://touchendocrinology.com/endocrine-oncology/journal-articles/a-new-medical-therapy-for-multiple-endocrine-neoplasia-type-1/

  Basic science studies have indicated a specific dependence of MEN1-mutated cells on an enzyme involved in pyrimidine synthesis, and positive results were seen in a limited number of patients treated with a re-purposed agent that blocks this enzyme. […] The overactivation of DHODH in MEN1-mutant cells appears to indicate particular dependence on this enzyme in such cells, and offers a relatively specific route to such oncogenic addiction. […] The results of the study demonstrate that leflunomide may be an effective drug for the treatment of MEN1-mutated tumours. […] Leflunomide can achieve targeted killing of early tumours with a small size and few mutations, thus suggesting early therapeutic intervention and effective prevention.

• #2

  https://journals.lww.com/md-journal/fulltext/2021/12100/a_case_report_of_multiple_endocrine_neoplasia_type.61.aspx

  In recent years, experimental data revealed a new possible role of MENIN in autoimmunity, in which MENIN-deficient CD4 and CD8 lymphocytes are prone to dysfunction and trigger autoimmune disorders. […] Thus, MENIN-deficient T lymphocytes evolve to a dysfunctional pattern prone to autoimmunity, and this may be the basis for the constellation of autoimmune manifestations present in our index patient. […] Future cumulative clinical data may shed light on the possible role of MEN1 mutations (and type of mutations) in predisposing carriers to autoimmunity as well as for a certain phenotype, which may have implications for targeted life-long surveillance and treatment.

• #3 Frontiers | Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00339/full

  Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. […] MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. […] The MEN1 gene, located on chromosome 11 (11q13), was first identified in 1997, and spans ~9,000 base pairs of genomic DNA containing 10 exons. This gene encodes the protein menin. […] The majority of MEN1 germline mutations (69%) are predicted to be pathogenic due to either premature truncation of menin due to frame-shift mutations (42%) and nonsense mutations (14%), or exon region deletions which are attributed to splicing defects (10.5%) and large deletions (2.5%).

• #3 Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype–phenotype correlation | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-variable-clinical-expression-in-patients-S1807593222023961

  To date, a clear correlation between genetic events and the variable clinical expression of MEN1 has not been established. Further understanding of the genetic aspects of MEN1 and the pathogenesis of MEN1-related tumors could enable more tailored clinical screening and treatment strategies. […] In MEN1 tumors, inactivating mutations in the MEN1 gene result in alterations of histone protein modifications: both deacetylation and trimethylation are repressed. In this way, the normal function of menin acting as co-repressor and co-activator of gene transcription is disabled. Consequently, the normal function of menin (preservation of differentiation of the cell by modification of histone proteins and transcription of genes responsible for inhibition of cell division) is defective. […] A MEN1 gene mutation may be completely detrimental to gene function. It may also result in a protein product with some residual function. An aberrant menin protein may be impaired in its function by several mechanisms: menin can interact with many different proteins.

• #3 Multiple endocrine neoplasia type 1 (MEN1): Not only inherited endocrine tumors | Genetics in Medicine

  https://www.nature.com/articles/gim2009126

  An additional clue for a role of p18 and p27 in MEN1 pathophysiology comes from the studies in knockout mice, in which the simultaneous loss of p18 and p27, CDKI, leads to a tumor spectrum similar to that in human MEN1 and MEN2 patients, including tumors in the pituitary, parathyroid, thyroid, endocrine pancreas, stomach, and duodenum. […] However, it still remains to be delineated what determines the tissue-specific activities of menin and whether the menin-MLLHox pathway has a role in suppressing tumorigenesis in endocrine organ.

• #3 MEN1 (multiple endocrine neoplasia I)

  https://atlasgeneticsoncology.org/gene/148/men1-(multiple-endocrine-neoplasia-i)

  MEN1 is highly penetrant and more than 90% of gene-carriers will present biological and/or clinical signs of the disease affter the fifth decade; around 5-10% of patients have an agressive disease before age 20 no genotype-phenotype correlation were found to date in MEN1; nevertheless, most families with agressive NET have truncating mutations either in exons 2, 3, 9 or 10 but no studies have been able to find statistical evidence of this putative correlation; recent investigations suggested that some MEN1 families could express only primary hyperparathyroidism, so called familial primary hyperparathyroidism (FIHPT), an allelic variant of MEN1; MEN1 related FIHPT appears as a benign disease but hyperplasia and/or adenoma occur in all parathyroid glands; recent data suggest that this variant could be associated to missense mutations in exons 4 to 7 of the MEN1 sequence; nevertheless, such correlations remain uncertain an do not have clinical implications in medical practice; the identification of germline missense mutations in exons 4 to 7 must lead to an extensive biological and clinical screening of patients in order to exclude the occurrence of pancreatic and pituitary disease, as recently shown in a typical MEN1 family carrying a Leu264Pro in exon 5; approximately 10-15% of MEN1 families do not show any mutation in the known part of MEN1 sequence; clinical profile in these families do not differ from that of families with identified mutations and it is therefore possible that MEN1 mutations occur outside the coding sequence; deletion of part or full MEN1 sequence has been also suggested as a rare mechanism of germline mutation

• #4 Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype–phenotype correlation | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-variable-clinical-expression-in-patients-S1807593222023961

  The type of missense mutation may have a differential effect on the function of menin: in-frame or missense mutations differ from frameshift/nonsense mutations, whereas missense and in-frame mutations may affect the interactions of a menin domain with transcription factors such as JunD, Smad3 and NFkappaB and nuclear receptors, or impair sensitization to apoptosis from caspase-3, p53 or p21. […] In MEN1 disease-gene carriers, all vitamin D receptors and peroxisome proliferator-activated receptors are expressed but are probably less activated because of impaired menin function. […] The difference in clinical expression between the genders may be explained by the difference in transcription regulation of estrogen and androgen receptors. Menin can act as a co-activator of nuclear hormone receptors including estrogen and possibly androgen receptors.

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