Advances in multiple endocrine neoplasia type 1 (MEN1)
Author: Magnus Nordenskjöld, Ertilh Ambercer & Kjell Öberg (Organizers of the 5th Znternational Workshop on MEN)
References: Journal of Internal Medicine 1995; 238: 231-232
In the last couple of years, molecular genetics has been brought into the hospital wards at an increasing pace. This Minisymposium compiles the current knowledge of the inherited cancer predisposition, multiple endocrine neoplasia type 1 (MEN1). The following articles demonstrate how this development has begun to change the management of the patients and their relatives. Familial aggregation of patients with multiple endocrine tumours had already been observed at the beginning of this century.
Some 40 years ago, family studies led to the distinction of two autosomal dominant tumour predisposition syndromes, MEN1 and MEN2. MENl (Werner’s syndrome) associates parathyroid tumours, pancreatic islet hyperplasia progressing to carcinoma and pituitary adenomas. Common pancreatic lesions are gastrinomas (Zollinger-Ellison syndrome) and insulinomas and the most common pituitary lesion is prolactinoma. With family registers and biochemical screening of ‘ at-risk’ individuals, affected family members can be identified before the lesions give clinical symptoms. This has improved both the quality of life and survival of patients with MEN1 .
However, the type of biochemical screening and the treatment strategies for MEN1 is still subject to considerable controversy. The experiences from different clinical programmes are summarized in this Minisymposium. The family registers for MEN1 were the key to the understanding of the pathogenesis of the disorder. In 1988, family studies led to the location of the MEN1 gene to chromosome 11 by linkage to polymorphic DNA markers. For MEN1, the first studies also revealed the mechanism behind the disease, because type 1 in MEN1-associated tumours indicated loss of function consistent with the MEN1 gene being a tumour-suppresser gene. Numerous family studies have since confirmed and refined the location of the MEN1 gene to a small region within chromosome band 11q13. Recent development now provides an arsenal of molecular tools which will allow predictive testing for MEN1 in affected families. These tests are based on linked genetic markers, and are thus indirect predictors for a genetic predisposition.
The use of these tests and a detailed description of the different tools for MEN1 testing are outlined. One of the aims of the MEN Workshop (The 5th International Workshop on Multiple Endocrine Neoplasia (MEN), held outside Stockholm, 29 June-2 July 1994) was of course to discuss the disease genes, their properties and mode of action. Although several groups are hunting for the MEN1 gene, no conclusive evidence linking an inherited genetic lesion within a specific gene to the disease was presented. This final breakthrough must wait until the different ‘candidate genes ‘ within the restricted MEN1 region on chromosome 11 have been scrutinized in detail and one unquestionable candidate identified.
One way to peruse the further outlining of inherited disorders and the mechanisms involved will be to construct animal models by transgene technology. The paper by Kumar et al. focuses on constriction of knock outs for tumour suppresser genes as a general approach. This will no doubt be an important tool for understanding the basic mechanisms for MEN1 and the normal rule of the disease gene.
Multiple Endocrine Neoplasia Type 1: Latest Insights
Author: Maria Luisa Brandi (University of Florence, Firenze, Italy), Sunita K. Agarwal (National Institutes of Health, Bethesda, USA), Nancy D. Perrier (The University of Texas MD Anderson Cancer Center, Houston, USA; ) Kate E. Lines (University of Oxford, Oxford, UK), Gerlof D. Valk (University Medical Center Utrecht, Utrecht, the Netherlands), Rajesh V. Thakker (University of Oxford, Oxford, UK)
References: Endocrine Reviews, 2021, Vol. 42, No. 2, 133–170 doi:10.1210/endrev/bnaa031
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.
Multiple endocrine neoplasia type 1 (MEN1) and the pancreas.
Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome – An International Consensus Statement
Author: Bruno Niederlea, Andreas Selberherra, Detlef K. Bartschb, Maria L. Brandic, Gerard M. Dohertyd, Massimo Falconie, Pierre Goudetf, Thorvardur R. Halfdanarsong, Tetsuhide Itoh, Robert T. Jenseni, Al- berto Larghij, Lingaku Leei, Kjell Öbergk, Marianne Pavell, Aurel Perrenm, Samira M. Sadowskin, Francesco Tonellio, Frédéric Triponezp, Gerlof D. Valkq, Dermot O’ Tooler, David Scott-Coombess, Rajesh V. Thakkert, Geoffrey Thompsonu, Giorgio Tregliav, Bertram Wiedenmannw
References: Neuroendocrinology 2021;111(7):609-630. doi: 10.1159/000511791. Epub 2020 Sep 24.
ABSTRACT
The better understanding of the biological behavior of MEN1 organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. DP-NENs are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to re- evaluate recommendations for their diagnosis and treatment. Especially over the last two years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP- NENs.
It was the aim of the international consortium of experts in endocrinology, genetics, radiology, sur- gery, gastroenterology and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a “logbook” for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long- term treatment results in these rare tumors.
The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and in- ternational societies.
When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review
Author: Benjamin Chevalier, Lucie Coppin, Pauline Romanet, Thomas Cuny, Jean-Christophe Maïza, Juliette Abeillon, Julien Forestier, Thomas Walter, Olivier Gilly, Maëlle Le Bras, Sarra Smati, Marie Laure Nunes, Aurore Geslot, Solange Grunenwald, Céline Mouly, Gwenaelle Arnault, Kathy Wagner, Eugénie Koumakis, Christine Cortet-Rudelli, Émilie Merlen, Arnaud Jannin, Stéphanie Espiard, Isabelle Morange, Éric Baudin, Mathias Cavaille, Igor Tauveron, Marie-Pierre Teissier, Françoise Borson-Chazot, Delphine Mirebeau-Prunier, Frédérique Savagner, Éric Pasmant, Sophie Giraud, Marie-Christine Vantyghem, Pierre Goudet, Anne Barlier, Catherine Cardot-Bauters, and Marie Françoise Odou
References: The Journal of Clinical Endocrinology & Metabolism, 2024, 109, e1482–e1493
ABSTRACT
Context: germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear.
Objective: to evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients.
Design: retrospective observational nationwide study. Narrative review of literature and variant class reassessment.
Patients: we included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database.
Results: from 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis.
Conclusion: the prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families..