Publication

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

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., Rinkes, I. H. M. B., Timmers, H. T. M., Valk, G. D. & Vriens, M. R., Sep-2018, In : European Journal of Endocrinology. 179, 3, p. 153-160 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • E. B. Conemans
  • L. Lodewijk
  • C. B. Moelans
  • G. J. A. Offerhaus
  • C. R. C. Pieterman
  • F. H. Morsink
  • O. M. Dekkers
  • W. W. de Herder
  • A. R. Hermus
  • A. N. van der Horst-Schrivers
  • M. L. Drent
  • P. H. Bisschop
  • B. Havekes
  • L. A. A. Brosens
  • K. M. A. Dreijerink
  • I. H. M. Borel Rinkes
  • H. Th M. Timmers
  • G. D. Valk
  • M. R. Vriens

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 MEN 1-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
Publication statusPublished - Sep-2018

    Keywords

  • PROMOTER HYPERMETHYLATION, CANCER, MENIN, EXPRESSION, GENES, HEREDITARY, PATHOLOGY, MUTATION, PATHWAY, MGMT

View graph of relations

ID: 75926617