The future: genetics advances in MEN1 therapeutic approaches and management strategies

Abstract

The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13, predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies, and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin, and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.

Pancreatic Neuroendocrine Neoplasms: Landscape and Horizon

“…All of the 4 conditions are inherited as autosomal dominant disorders. The frequencies of PanNET are higher in MEN1 (30%-80%) and VHL (17%) 27,28 ; they are extremely rare in NF1 and TSC. 29 However, NF1-associated duodenal and ampullary somatostatinoma is more common.…”

Theranostik von neuroendokrinen Tumoren

“…Im Rahmen des MEN1-oder Wermer-Syndroms treten bei über 90 % der Patienten Nebenschilddrüsenadenome auf, bei etwa 50 % der Patienten neuroendokrine Tumore des Vorderdarms (v. a. des Magens und Pankreas) und bei 40 % Tumore der Hypophyse [12]. Das MEN1-Syndrom ist selten mit einer Prävalenz von etwa 1:30 000 und wird in 70 -90 % der Fälle durch Mutationen des Tumorsupressor-Gens MEN1 verursacht [13]. Das von MEN1 kodierte Protein Menin wird im Zellkern exprimiert und besitzt zahlreiche Funktionen, die durch verschiedene Mutationen gestört werden können.…”

Happy 20th anniversary MEN1: from positional cloning to gene function restoration

“…We are delighted that one of the co-authors of this original publication Sunita Agarwal, then a postdoctoral fellow at the NIDDK, NIH, has graced us with an insightful and comprehensive overview on the genetic aspects of MEN1 and how these influence the clinical management of patients with MEN1 ( Fig. 2) (Agarwal 2017).…”

“…The review articles cover the broad range of MEN1 syndrome and focus on the clinical (Manoharan et al 2017, Marini et al 2017, van Leeuwaarde et al 2017, translational (Agarwal 2017, Alrezk et al 2017 and basic scientific , Feng et al 2017, Mohr & Pellegata 2017 aspects; therefore, they provide a comprehensive update on MEN1. We are delighted that several of the scientists that pioneered MEN1 research provided their expertise to this special issue.…”

“…Link to the PYGM locus Byström et al 1990 1996 Integrated map of the MEN1 region Courseaux et al 1996 1997 1990 Genetic map of 11q13 Julier et al 1990 1991 Physical map of 11q13 Janson et al 1991 24:10 of patients with MEN1, several reviews in this series highlight the importance of genetic counseling (Agarwal 2017, Marini et al 2017, van Leeuwaarde et al 2017. In a previous article, Valk and coworkers showed that today, the correct diagnosis of MEN1 frequently remains substantially delayed.…”