Multiple Endocrine Neoplasia Type 1: Latest Insights

Abstract

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. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. 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 β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.

Keywords: MEN1; epigenetics; menin; mouse models; mutation-negative; neuroendocrine tumors; pharmacological therapies; phenocopy; quality of life; surgical approaches.

Graphical Abstract

Figure 1.

Tumors associated with MEN1.

Figure 2.

Three-dimensional crystal structure of human menin alone or together with interacting partners. A, Structure of menin showing a pocket/cavity for protein-protein interaction (Protein Data Bank; PDB ID 3U84). The different domains of menin are color coded: “N-terminus” in pale green (1-101), “thumb” in green-cyan (102-230), “palm” in olive green (231-386), and “fingers” in dark green (387-end). B, Structure of menin interacting with the menin-binding motif (MBM) of JUND (amino acid 27-47, in purple) (PDB ID 3U86). C, Structure of menin interacting with the MBM of MLL1 (amino acid 6-13, in gold) (PDB ID 3U85). D, The ternary complex of menin with interacting regions in LEDGF (amino acid 347-435, in red) and MLL1 (MBM-LEGDF binding motif [LBM], amino acid 6-153, in gold) (PDB ID 3U88). To facilitate crystallization, the following regions were deleted (and not present in the structures shown in this figure): an unstructured loop (amino acid 460-519) in menin, a short fragment (amino acid 40-45) in the JUND-MBM and 2 loop regions (amino acids 16-22 and 36-102) in the MLL1-MBM-LBM. Structural images were generated by using PyMOL (Schrodinger Inc; https://pymol.org).

Figure 3.

Schematic representation of epigenetic regulation in multiple endocrine neoplasia type 1 (MEN1)-associated tumors. Epigenetic modification in normal cells is shown on the left. Aberrant epigenetic change observed or predicted after menin loss in tumors is shown in the middle. Consequence of the aberrant epigenetic change is shown on the right. Green and red indicates the nature of the specific histone or DNA epigenetic modification, active or repressive mark of gene expression, respectively. Open black oval with a slanted line indicates loss of that histone mark. Alternative lengthening of telomeres (ALT) is activated in tumors and it is absent in normal cells (indicated by the blue open oval with a slanted line). Not shown is miR-24–mediated epigenetic regulation.

Figure 4.

Percentage distribution of the different types of MEN1 mutations. Obvious inactivation of menin is predicted by nonsense, frameshift, and splice mutations, and large deletions that constitute 69% of the mutations. Missense and in-frame insertion or deletion (indel) mutations are sliced out of the pie chart to indicate the potential of variants of unknown significance among these 2 types of mutations.

Figure 5.

Schematic diagram for a suggested approach to germline genetic screening in MEN1 and MEN1-like disease. MEN1: a patient with 2 or more MEN1-associated endocrine tumors. MEN1-like: a patient with as few as any 1 of the 3 main MEN1-associated endocrine tumors. Clinical MEN1: patients with MEN1 or MEN1-like disease features. Genetic MEN1: germline MEN1 mutation-positive. WES, whole-exome sequencing; WGS, whole-genome sequencing; +ve, genetic test is positive; -ve, genetic test is negative, and +ve*, genetic test is positive as per American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines.

Figure 6.

Intraoperative view after robotic pancreaticoduodenectomy of a pancreatic neuroendocrine tumor (pNET) in the head of the pancreas before reconstruction. CHA, common hepatic artery; IVC, inferior vena cava; SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Figure 7.

Emerging therapies for MEN1. Menin, encoded by the MEN1 gene, has roles in multiple pathways associated with cell proliferation. These can be targeted by emerging compounds, including receptor tyrosin kinase (RTKs) inhibitors, novel mechanistic target of rapamycin (mTOR) inhibitors, β-catenin antagonists, epigenetic modulators, and thrombospondin analogues. In addition, preclinical studies indicate MEN1 gene replacement may have efficacy in MEN1 patients, and somatostatin (SST) analogues may have chemopreventive efficacy.