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Wenzel M Hackeng, Lodewijk A A Brosens, and Koen M A Dreijerink

Insulinomas are rare functional pancreatic neuroendocrine tumors. While most insulinomas are indolent and cured after surgery, 10–15% of cases show aggressive or malignant tumor behavior and metastasize locally or to distant organs. Patients with metastatic insulinoma survive significantly shorter. Recognizing aggressive insulinomas can help to predict prognosis, guide therapy and determine follow-up intensity after surgery. This review offers a summary of the literature on the significant clinical, pathological, genetic and epigenetic differences between indolent and aggressive insulinomas. Aggressive insulinomas are characterized by rapid onset of symptoms, larger size, expression of ARX and alpha-1-antitrypsin and decreased or absent immunohistochemical expression of insulin, PDX1 and GLP-1R. Moreover, aggressive insulinomas often harbor ATRX or DAXX mutations, the alternative lengthening of telomeres phenotype and chromosomal instability. Tumor grade and MEN1 and YY1 mutations are less useful for predicting behavior. Aggressive insulinomas have similarities to normal alpha-cells and non-functional pancreatic neuroendocrine tumors, while indolent insulinomas remain closely related to normal beta-cells. In conclusion, indolent and aggressive insulinoma are different entities, and distinguishing these will have future clinical value in determining prognosis and treatment.

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Koen M A Dreijerink, H T Marc Timmers, and Myles Brown

Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin-modifying enzymes, in particular, the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next-generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin. We propose that menin regulates cell type-specific transcriptional programs by linking chromatin regulatory complexes to specific transcription factors. In this fashion, the MEN1 gene is a tumor suppressor gene in the endocrine tissues that are affected in MEN1. Recent studies have hinted at possibilities to pharmacologically restore the epigenetic changes caused by loss of menin function as therapeutic strategies for MEN1, for example, by inhibition of histone demethylases. The current lack of appropriate cellular model systems for MEN1-associated tumors is a limitation for compound testing, which needs to be addressed in the near future. In this review, we look back at the past twenty years of research on menin and the mechanism of disease of MEN1. In addition, we discuss how the current understanding of the molecular function of menin offers future directions to develop novel treatments for MEN1-associated endocrine tumors.