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

in European Journal of Endocrinology
Correspondence should be addressed to M R Vriens; Email: mvriens@umcutrecht.nl
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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.

Downloadable materials

  • Supplementary table 1

 

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Figures

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    Promoter methylation of CASP8. (A) In MEN1-related (n = 61) and sporadic PanNETs (n = 34, P = 0.002). (B) In MEN1-related (n = 61) and sporadic PanNETs after subdividing sporadic PanNETs into menin-negative (n = 10) and menin-positive tumors (n = 13), (P = 0.046). Dotted line represents cut-off value for hypermethylation (15%).

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    Promoter hypermethylation of genes in both MEN1-related and sporadic PanNETs. Cut-off value for promoter hypermethylation was 15%. Only gene loci with hypermethylation in >10% of the MEN1-related tumors are shown.

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    Promoter methylation of MGMT in MEN1-related insulinomas and non-functioning PanNETs. Dotted line represents the 15% cut-off value for hypermethylation (P = 0.022).

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    Promoter hypermethylation and protein expression of VHL differs between different PanNETs of the same MEN1 patient. (A) VHL protein expression is lost in the PanNET with promoter hypermethylation of VHL. (B) In another PanNET of the same patient without promoter hypermethylation of VHL, protein expression is retained. Magnification 200×.

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