Opinion Article, J Clin Image Case Rep Vol: 8 Issue: 4

Molecular Mechanisms Underlying Multiple Endocrine Neoplasia (MEN)

Katie Gillis^*

¹Department of Endocrinology, Odense University Hospital, Denmark

*Corresponding Author: Katie Gillis,
Department of Endocrinology, Odense University Hospital, Denmark
E-mail: gilliskatie@gmail.com

Received date: 22 July, 2024, Manuscript No. CICR-24-150607;

Editor assigned date: 24 July, 2024, PreQC No. CICR-24-150607 (PQ);

Reviewed date: 07 August, 2024, QC No. CICR-24-150607;

Revised date: 14 August, 2024, Manuscript No. CICR-24-150607 (R);

Published date: 21 August, 2024, DOI: 10.4172/CICR.1000316

Citation: Gillis K (2024) Molecular Mechanisms Underlying Multiple Endocrine Neoplasia (MEN). J Clin Image Case Rep 8:4.

Description

Multiple Endocrine Neoplasia (MEN) refers to a group of inherited disorders that cause the development of tumors in multiple endocrine glands. These tumors can be benign or malignant, often leading to overproduction of hormones and associated health complications. MEN is broadly classified into two major types: MEN type 1 (MEN1) and MEN type 2 (MEN2), with each type involving specific genetic mutations that lead to the development of endocrine tumors. Understanding the molecular mechanisms that underlie MEN is essential for diagnosing, managing and treating these syndromes.

Mutations in the MEN1 gene and tumorigenesis

MEN1, also known as Wermer’s syndrome, is caused by mutations in the MEN1 gene, which is a tumor suppressor gene located on chromosome 11. The MEN1 gene encodes a protein called menin, which plays an importana role in regulating cell growth, differentiation and gene transcription. Menin functions as a scaffold protein that interacts with various other proteins, including histone modifiers and transcription factors, to control cellular proliferation and maintain genomic stability.

Mutations in the MEN1 gene lead to the loss of menin’s tumorsuppressive functions, resulting in unregulated cell growth and the development of tumors in endocrine tissues. These mutations are typically loss-of-function mutations, meaning they inactivate the MEN1 gene. Since menin is a tumor suppressor, both copies of the MEN1 gene (one from each parent) must be mutated or inactivated for tumorigenesis to occur, following Knudson’s two-hit hypothesis. This means that individuals with MEN1 inherit one defective copy of the MEN1 gene and tumor formation occurs when the second copy is lost or mutated in specific cells during their lifetime.

Parathyroid glands: Hyperparathyroidism, caused by parathyroid tumors, is one of the earliest and most common manifestations of MEN1. These tumors cause overproduction of Parathyroid Hormone (PTH), leading to hypercalcemia, which can result in kidney stones, bone pain and other symptoms associated with calcium dysregulation.

Pancreatic islet cells: Tumors in the pancreas, particularly gastrinomas and insulinomas, are also common in MEN1. These tumors cause overproduction of hormones like insulin and gastrin, leading to symptoms such as hypoglycemia (from insulin overproduction) and peptic ulcers (from excessive gastric acid due to gastrin overproduction).

Pituitary gland: Pituitary tumors in MEN1 often lead to excessive production of hormones such as prolactin, growth hormone, or Adrenocorticotropic Hormone (ACTH), resulting in conditions like prolactinomas, acromegaly, or Cushing’s disease.

At the molecular level, menin’s role in regulating transcription factors and chromatin remodeling is critical for controlling the expression of genes involved in cell cycle regulation and apoptosis. Loss of menin function disrupts these pathways, leading to uncontrolled cellular proliferation and the formation of endocrine tumors. Moreover, menin has been shown to interact with MLL1 (mixed-lineage leukemia 1), a histone methyltransferase, to regulate the transcription of key genes involved in tumor suppression. In MEN1, the loss of menin-MLL1 interaction contributes to tumorigenesis by allowing the unchecked expression of oncogenes.

MEN2: RET proto-oncogene mutations and oncogenesis

MEN2 is characterized by mutations in the RET proto-oncogene, located on chromosome 10, which encodes a receptor tyrosine kinase involved in cell growth, differentiation and survival. Unlike MEN1, where tumorigenesis is driven by the loss of tumor suppressor function, MEN2 is caused by gain-of-function mutations in the RET gene, leading to constitutive activation of the RET protein. This results in continuous signaling through pathways like the MAPK/ERK and PI3K/AKT pathways, which promote cell proliferation and survival.

The RET protein functions by binding to ligands like Glial cell line- Derived Neurotrophic Factor (GDNF), leading to receptor dimerization and autophosphorylation of tyrosine residues in its intracellular domain. This phosphorylation event triggers the activation of downstream signaling cascades that promote cell survival and proliferation. In MEN2, mutations in the RET gene result in ligand-independent activation of the receptor, causing continuous signaling even in the absence of external growth factors. This unregulated signaling leads to the unchecked growth of endocrine cells and the development of tumors, particularly in the thyroid and adrenal glands.

Multiple Endocrine Neoplasia (MEN) is a complex group of hereditary disorders driven by distinct molecular mechanisms. In MEN1, the loss of tumor suppressor function due to mutations in the MEN1 gene leads to the uncontrolled growth of endocrine cells, while in MEN2, gain-of-function mutations in the RET proto-oncogene result in continuous activation of oncogenic pathways. These molecular insights have not only enhanced our understanding of the pathogenesis of MEN but also paved the way for more targeted and personalized treatment strategies. By identifying the specific genetic mutations underlying MEN, clinicians can tailor treatment approaches to the molecular profile of each patient, improving outcomes and offering hope for better management of these complex disorders.