A small step for man, a giant leap for MEN kind: The translational approach

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome. Primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (DP-NETs) and pituitary adenomas are the main manifestations. The discovery of the responsible gene named MEN1in 1997 was a starting point for the evolving efforts to understand MEN1 disease from a molecular and clinical perspective. Evidence-based clinical practice guidelines provide guidance to health care professionals for MEN1 patient management in general, but offering personalized care is still challenging. Metastatic duodenopancreatic NETs (DP-NETs) are the most frequent cause of death in MEN1. The main challenge is to identify the patients at risk for aggressive tumor behavior and to select the most effective therapy with minimal morbidity. Currently, there are no targeted therapies directed toward restoration of function of menin, the protein product of MEN1. Unravelling the biological processes and oncogenic pathways involved in tumorigenesis in MEN1 patients is needed for the development of prognostic markers as well as novel therapeutic targets for advanced disease. All the efforts made in MEN1 research may also be of importance for sporadic PanNET cases with somatic MEN1mutations, as 40% of these tumors harbor somatic inactivating mutations of this gene.

This thesis aims to provide steps forward towards a translational approach in MEN1-related PanNET research. In this thesis special attention is paid to epigenetic factors contributing to tumor development as menin is known to be involved in epigenetic regulation. Potential new therapeutic targets are highlighted. The nationwide DutchMEN1 Study Group (DMSG) database forms a solid basis for clinical data used in this thesis. This database is unique for its unselected patient cohort and long-term follow up data. Furthermore, tissue blocks from nearly all MEN1 patients who underwent pancreatic surgery for PanNETs were collected.

We found that cyclin-dependent kinase inhibiting compounds are a class of drugs that can be considered as a potential targeted therapy, as MEN1-related PanNETs show loss of p18Ink4c expression. DNA promoter methylation could also be a therapeutic target for advanced disease as methylation of the DNA promoter is a common event in PanNETs in MEN1, especially in large tumors and in tumors concurrent with liver metastases. From a clinical perspective it is important to note that, although progression of liver metastases form DP-NETs in MEN1 can be fairly slow, life expectancy of this relatively young patient group is clearly reduced. These data highlight the importance of individualization of patient care. Last but not least, our finding that breast cancer is a MEN1 manifestation is of great importance for female MEN1 patients with direct consequences for the care of these patients.

In conclusion, personalized care for MEN1 patients is an absolute necessity. Giant leaps forward have already been taken, but future research efforts should focus on further improvements. Due to the rarity of MEN1 syndrome, international collaboration is of key importance for performing high quality research. Furthermore, pre-clinical models are needed to be able to test potential (epigenetic) treatments for PanNETs in MEN1.