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Updated: Feb 9, 2026

DNA Methylation: Bisulphite Modification and Analysis
Published on: October 21, 2011
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.
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.
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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