DNA Methylation Profiling in MEN1-related Pancreatic Neuroendocrine Tumors Reveals a Potential Epigenetic Target for Treatment

Eur J Endocrinol. 2018 Sep;179(3):153-160. doi: 10.1530/EJE-18-0195. Epub 2018 Jun 14.

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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics*
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Middle Aged
  • Multiple Endocrine Neoplasia Type 1 / genetics*
  • Neuroendocrine Tumors / genetics*
  • Pancreatic Neoplasms / genetics*
  • Promoter Regions, Genetic / genetics*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human