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

E B Conemans1,2,3, L Lodewijk1, C B Moelans4

  • 1Departments of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Abstract

Insights

Promoter hypermethylation is common in pancreatic neuroendocrine tumors (PanNETs), regardless of genetic cause. Targeting DNA methylation may offer therapeutic benefits for patients with advanced MEN1-related PanNETs.

Area of Science:

  • Oncology
  • Epigenetics
  • Genetics

Background:

  • Epigenetic alterations, specifically DNA promoter hypermethylation, are implicated in the development of pancreatic neuroendocrine tumors (PanNETs).
  • This gene silencing mechanism is potentially reversible, presenting a therapeutic target.
  • Multiple endocrine neoplasia type 1 (MEN1) is a primary genetic cause of inherited PanNETs.

Purpose of the Study:

  • To investigate and compare promoter methylation profiles in MEN1-related and sporadic PanNETs.
  • To identify specific genes and patterns of methylation associated with MEN1-related PanNETs.

Main Methods:

  • Methylation-specific multiplex ligation-dependent probe amplification was employed.
  • Assessed promoter methylation status of 56 tumor suppressor genes.
  • Analyzed 61 MEN1-related and 34 sporadic PanNETs, comparing cumulative methylation index (CMI), methylation percentages, and hypermethylation frequencies.

Main Results:

  • Promoter hypermethylation was frequently observed in both MEN1-related and sporadic PanNETs.
  • No significant difference in CMI was found between MEN1-related and sporadic PanNETs.
  • Higher methylation percentages of CASP8 were noted in MEN1-related PanNETs (59% vs 16.5%).
  • In MEN1-related non-functioning PanNETs, higher CMI correlated with larger tumor size (>2 cm) and presence of liver metastases.
  • MGMT2 hypermethylation was more prevalent in non-functioning PanNETs compared to insulinomas.

Conclusions:

  • Promoter hypermethylation is a common epigenetic event in both MEN1-related and sporadic PanNETs.
  • The findings suggest that targeting DNA methylation could be a valuable therapeutic strategy for MEN1 patients, particularly those with advanced PanNETs.

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