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 theMEN1gene 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 theMEN1gene in MEN1-target tissues. Therefore,MEN1is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by theMEN1gene, menin, holds true in mouse models with germline heterozygousMen1loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of theMen1gene. The availability of genetic testing for mutations in theMEN1gene 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 identifyMEN1germline 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.