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Updated: Nov 5, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Evaluation of MGMT Gene Methylation in Neuroendocrine Neoplasms
Rosa Della Monica1, Mariella Cuomo1, Roberta Visconti2
1CEINGE Biotecnologie AvanzateNaplesItaly.
Abstract:
Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O 6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.
Insights
MGMT methylation is a promising biomarker for predicting temozolomide response in neuroendocrine neoplasms (NENs). This study found methylation in 74% of NENs, suggesting its routine use for treatment selection.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Unresectable neuroendocrine neoplasms (NENs) exhibit poor response to conventional therapies.
- Temozolomide, an alkylating agent effective in glioblastomas, shows promise in advanced NENs.
- MGMT methylation status predicts temozolomide response in glioblastomas but is unvalidated in NENs.
Purpose of the Study:
- To investigate O6-methylguanine-DNA methyltransferase (MGMT) gene methylation in neuroendocrine neoplasms (NENs).
- To evaluate the utility of MGMT methylation as a predictive biomarker for temozolomide treatment in NENs.
- To compare methylation-specific PCR (MSP) and amplicon bisulfite sequencing (ABS) for MGMT methylation assessment in NENs.
Main Methods:
- Analyzed MGMT methylation in 42 NENs from diverse origins and grades using MSP and ABS.
- ABS employed high-resolution, next-generation sequencing for comprehensive CpG site interrogation.
- MSP, a standard glioblastoma method, was compared against ABS for NEN analysis.
Main Results:
- MGMT methylation was detected in 74% (31/42) of the investigated NENs.
- Higher MGMT methylation degrees were observed in well-differentiated tumors and gastrointestinal NENs.
- MSP analysis region was found sufficiently informative for MGMT methylation status in NENs.
Conclusions:
- MGMT methylation is prevalent in NENs and may serve as a predictive biomarker for temozolomide therapy.
- The standard MSP method is adequate for interrogating MGMT methylation in NENs.
- Routine assessment of MGMT methylation could guide temozolomide treatment selection in NEN patients.
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