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

• Published in: European journal of endocrinology Vol. 179; no. 3; pp. 153 - 160
• Main Authors: Conemans, E B, Lodewijk, L, Moelans, C B, Offerhaus, G J A, Pieterman, C R C, Morsink, F H, Dekkers, O M, de Herder, W W, Hermus, A R, van der Horst-Schrivers, A N, Drent, M L, Bisschop, P H, Havekes, B, Brosens, L A A, Dreijerink, K M A, Borel Rinkes, I H M, Timmers, H Th M, Valk, G D, Vriens, M R
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.09.2018; Oxford University Press
• Subjects: Adult; Aged; Aged, 80 and over; Clinical Study; Deoxyribonucleic acid; DNA; DNA fingerprinting; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic - genetics; Epigenetics; Female; Gene silencing; Genes; Genes, Tumor Suppressor; Humans; Liver; Male; Metastases; Middle Aged; Multiple endocrine neoplasia; Multiple Endocrine Neoplasia Type 1 - genetics; Neuroendocrine tumors; Neuroendocrine Tumors - genetics; Pancreas; Pancreatic Neoplasms - genetics; Promoter Regions, Genetic - genetics; Therapeutic applications; Tumor suppressor genes; Von Hippel-Lindau Tumor Suppressor Protein - genetics
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/EJE-18-0195

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.