The MEN1 gene is associated with autosomal dominant multiple endocrine neoplasia type 1 (MEN1) syndrome (MedGen UID: 9957) and familial isolated hyperparathyroidism (FIHP) (OMIM: 145000).
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The gene MEN1 encodes the menin protein, a putative tumor suppressor. Menin has been shown to localize to the nucleus and inhibit transcriptional activation by transcription factor JunD, but the function of this protein is largely unknown.
Multiple endocrine neoplasia type 1
MedGen UID: 9957
Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by varying combinations of parathyroid, pancreatic neuroendocrine, and anterior pituitary tumors, with 94% penetrance by age 50. Some individuals may also develop carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, and lipomas (PMID: 23565397, 11739416, 22723327, 26363542). Endocrine tumors become symptomatic due to hormone overproduction or by growth of the tumor itself (PMID: 20301710). Parathyroid tumors are the main MEN1-associated endocrinopathy, occurring in >95% of affected individuals (PMID: 22723327, 11739416). Primary hyperparathyroidism is usually the presenting symptom with the typical age of onset between 20 and 25 years of age (PMID: 26363542).
MEN1 syndrome is caused by mutations in the MEN1 gene. Pathogenic MEN1 variants have also been identified in individuals with familial isolated hyperparathyroidism (FIHP), which is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies (PMID: 11454510, 12213668, 12699448).
The MEN1 gene is a tumor suppressor gene that encodes the protein menin. Menin is a component of a histone methyltransferase complex, which methylates histone H3, suggesting that it functions as a transcriptional regulator. Menin also interacts with a large number of proteins that play a role in the inhibition of cell proliferation, genomic stability, and cell cycle control. The exact function of menin and the mechanism by which alterations in menin lead to endocrine tumors are still unclear (PMID: “(external)26363542”:http://ncbi.nlm.nih.gov/pubmed/26363542; UniProtKB – PO00255 [MEN1_HUMAN], http://www.uniprot.org/uniprot/O00255. Accessed August 2017; Genetics Home Reference. MEN1 gene. https://ghr.nlm.nih.gov/gene/MEN1. Accessed August 2017).
MEN1 syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, while some cases reportedly occur de novo (i.e., an individual with a pathogenic variant has parents who do not have it); however, that individual now has a 50% risk of passing it on to their offspring.
Guidelines for surveillance, clinical evaluation, and treatment of MEN1 are published by the National Comprehensive Cancer Network (NCCN; National Comprehensive Cancer Network. Neuroendocrine Tumors. Version 2.2016, Accessed August 16, 2017) and by Thakker et al. (PMID: 22723327).
Clinical evaluation at diagnosis of MEN1
Professional Consensus Guidelines (Thakker et al. PMID: 22723327)
Screening in individuals at high risk of developing MEN1
|Tumor||Age to begin (yr)||Biochemical test: plasma or serum (annually)||Imaging test (time interval)|
|20||Gastrin (± gastric pH)||None|
|5||Fasting glucose, insulin||None|
|<10||Chromogranin-A, pancreatic polypeptide, glucagon, vasocative intestinal peptide||MRI, CT, or endoscopic ultrasound (annually)|
|Pituitary||5||Prolactin, IGF-I||MRI (every 3 years)|
|Thymic or bronchial carcinoid||15||None||CT or MRI (every 1-2 years)|
|Adrenal||<10||None unless symptoms or signs of functioning tumor and/or tumor >1cm are identified on imaging||MRI or CT (annually with pancreatic imaging)|
Treatment of MEN1-associated tumors
Pancreatic neuroendocrine tumors:
Bronchial/thymic/gastric neuroendocrine tumors:
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.
It is advantageous to know if a pathogenic variant in the MEN1 gene is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Neuroendocrine Tumors V.2.2016. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed August 16, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.
Review date: August 2017
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|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|