Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1

Abstract

Pancreatic neuroendocrine tumors (pNETs) are a rare group of cancers accounting for about 1-2% of all pancreatic neoplasms. About 10% of pNETs arise within endocrine tumor syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1). pNETs affect 30-80% of MEN1 patients, manifesting prevalently as multiple microadenomas. pNETs in patients with MEN1 are particularly difficult to treat due to differences in their growth potential, their multiplicity, the frequent requirement of extensive surgery, the high rate of post-operative recurrences, and the concomitant development of other tumors. MEN1 syndrome is caused by germinal heterozygote inactivating mutation of the MEN1 gene, encoding the menin tumor suppressor protein. MEN1-related pNETs develop following the complete loss of function of wild-type menin. Menin is a key regulator of endocrine cell plasticity and its loss in these cells is sufficient for tumor initiation. Somatic biallelic loss of wild-type menin in the neuroendocrine pancreas presumably alters the epigenetic control of gene expression, mediated by histone modifications and DNA hypermethylation, as a driver of MEN1-associated pNET tumorigenesis. In this light, epigenetic-based therapies aimed to correct the altered DNA methylation, and/or histone modifications might be a possible therapeutic strategy for MEN1 pNETs, for whom standard treatments fail.

Keywords: MEN1 gene; Multiple Endocrine Neoplasia type 1 (MEN1); epigenetic factors; gene mutation; menin; pancreatic neuroendocrine tumors (pNETs).

Figure 1

Neuroendocrine tumors of the gastro-entero-pancreatic tract associated with MEN1 syndrome. Prevalence of these tumors in MEN1 patients is indicated between brackets. Type 2 gastric neuroendocrine tumors develop in MEN1 patients, as a consequence of Zollinster–Ellison syndrome (ZES) from duodenal and/or pancreatic gastrinomas; to date, little is known about the true prevalence of these gastric neuroendocrine lesions in MEN1 patients. Jensen et al. [5] indicated a prevalence of 7–35%. Recently, Manoharan et al. [8] demonstrated that type 2 gastric neuroendocrine tumors occur only in MEN1 patients with ZES, and less frequently than previously reported (5.3% of the total of MEN1 patients and 12.5% of MEN1 patients with ZES).

Figure 2

Schematic representation of menin-regulated pathways with a potential role in pNET tumorigenesis. Wild-type menin acts as a tumor suppressor for pNET development. It plays a role in chromatin remodeling and genomic stability and, via its direct interaction with the MLL1/MLL2 and DAXX-ATRX complexes, in histone methylation-driven gene transcription, and negatively regulates cell proliferation. Loss of wild-type menin results in an uncontrolled cell growth, leading to tumor development. The red X marks indicate the inhibition of a biological process (i.e., gene transcription, cell proliferation)