DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

Elfi B Conemans, Lutske Lodewijk, Cathy M Moelans, G Johan A Offerhaus, Carolina R C Pieterman, Folkert H Morsink, Olaf M Dekkers, Wouter W de Herder, Ad R Hermus, Anouk N A van der Horst-Schrivers, Madeleine L Drent, Peter H Bisschop, Bas Havekes, Lodewijk A A Brosens, Koen M A Dreijerink, Inne H M Borel Rinkes, H Th Marc Timmers, Gerlof D Valk, Menno R Vriens

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. Design and methods: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. Results: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. Conclusion: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Original languageEnglish
Pages (from-to)153-160
Number of pages8
JournalEuropean Journal of Endocrinology
Volume179
Issue number3
Early online date14 Jun 2018
DOIs
Publication statusPublished - 1 Sept 2018

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