The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents
Abstract MGMT-promoter methylation is associated with favorable outcome in glioblastoma. The aim of this study was to determine whether the absolute number of methylated Cytosine-Guanine-dinucleotide-(CpG-)sites within the DMR-2 island of the MGMT-promoter may correlate with outcome in a qualitative...
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BMC
2021-03-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-021-01134-5 |
| _version_ | 1818676411909537792 |
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| author | Sebastian Siller Michael Lauseker Philipp Karschnia Maximilian Niyazi Sabina Eigenbrod Armin Giese Joerg-Christian Tonn |
| author_facet | Sebastian Siller Michael Lauseker Philipp Karschnia Maximilian Niyazi Sabina Eigenbrod Armin Giese Joerg-Christian Tonn |
| author_sort | Sebastian Siller |
| collection | DOAJ |
| description | Abstract MGMT-promoter methylation is associated with favorable outcome in glioblastoma. The aim of this study was to determine whether the absolute number of methylated Cytosine-Guanine-dinucleotide-(CpG-)sites within the DMR-2 island of the MGMT-promoter may correlate with outcome in a qualitative or quantitative fashion. In a cohort of newly diagnosed glioblastoma patients treated with stereotactic biopsy or open tumor resection plus concomitant chemoradiotherapy, we assessed MGMT-promoter methylation by methylation-specific polymerase-chain-reaction (MSP). Methylation of the CpG-sites 74–98 within the MGMT-promoter region was additionally analysed by Sanger sequencing, and the total number of methylated CpG-sites was correlated with outcome using proportional hazards models. 215 patients with glioblastoma were identified and stratified per MSP (positive: 53%, negative: 47%). Among MSP-positive tumors, hierarchical clustering identified three subgroups with different methylation rates (median: 80% vs. 52% vs. 47%), indicating a site-dependent methylation propagation. The methylation status of a given CpG-site indicated a neighborhood-dependent methylation propagation. Survival was linearly associated with the cumulative number of methylated CpG-sites. This was particularly true in patients who received at least one adjuvant cycle of temozolomide. Notably, all CpG-sites analyzed contributed similarly to effect size; this enabled a further predictive substratification of MSP-positive tumors with median OS ranging from as low as 17.1 months (< 18 methylated CpG-sites) to as high as 26.2 months (≥ 18 methylated CpG-sites) in the overall cohort. All in all, total number of methylated CpG-sites may correlate with outcome in a linear fashion. Such analysis may therefore add further predictive value to conventional methods of determining the MGMT-promoter status. |
| first_indexed | 2024-12-17T08:43:03Z |
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| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-17T08:43:03Z |
| publishDate | 2021-03-01 |
| publisher | BMC |
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| series | Acta Neuropathologica Communications |
| spelling | doaj.art-0462d463d218450c89160211d99395932022-12-21T21:56:17ZengBMCActa Neuropathologica Communications2051-59602021-03-019111110.1186/s40478-021-01134-5The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agentsSebastian Siller0Michael Lauseker1Philipp Karschnia2Maximilian Niyazi3Sabina Eigenbrod4Armin Giese5Joerg-Christian Tonn6Department of Neurosurgery, University Hospital, LMU MunichInstitute for Medical Information Processing, Biometry and Epidemiology, LMU MunichDepartment of Neurosurgery, University Hospital, LMU MunichGerman Cancer Consortium (DKTK)Center for Neuropathology and Prion Research, University Hospital, LMU MunichCenter for Neuropathology and Prion Research, University Hospital, LMU MunichDepartment of Neurosurgery, University Hospital, LMU MunichAbstract MGMT-promoter methylation is associated with favorable outcome in glioblastoma. The aim of this study was to determine whether the absolute number of methylated Cytosine-Guanine-dinucleotide-(CpG-)sites within the DMR-2 island of the MGMT-promoter may correlate with outcome in a qualitative or quantitative fashion. In a cohort of newly diagnosed glioblastoma patients treated with stereotactic biopsy or open tumor resection plus concomitant chemoradiotherapy, we assessed MGMT-promoter methylation by methylation-specific polymerase-chain-reaction (MSP). Methylation of the CpG-sites 74–98 within the MGMT-promoter region was additionally analysed by Sanger sequencing, and the total number of methylated CpG-sites was correlated with outcome using proportional hazards models. 215 patients with glioblastoma were identified and stratified per MSP (positive: 53%, negative: 47%). Among MSP-positive tumors, hierarchical clustering identified three subgroups with different methylation rates (median: 80% vs. 52% vs. 47%), indicating a site-dependent methylation propagation. The methylation status of a given CpG-site indicated a neighborhood-dependent methylation propagation. Survival was linearly associated with the cumulative number of methylated CpG-sites. This was particularly true in patients who received at least one adjuvant cycle of temozolomide. Notably, all CpG-sites analyzed contributed similarly to effect size; this enabled a further predictive substratification of MSP-positive tumors with median OS ranging from as low as 17.1 months (< 18 methylated CpG-sites) to as high as 26.2 months (≥ 18 methylated CpG-sites) in the overall cohort. All in all, total number of methylated CpG-sites may correlate with outcome in a linear fashion. Such analysis may therefore add further predictive value to conventional methods of determining the MGMT-promoter status.https://doi.org/10.1186/s40478-021-01134-5GlioblastomaMGMT promoterMethylation statusTemozolomideLinear correlationMethylation-specific polymerase-chain-reaction |
| spellingShingle | Sebastian Siller Michael Lauseker Philipp Karschnia Maximilian Niyazi Sabina Eigenbrod Armin Giese Joerg-Christian Tonn The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents Acta Neuropathologica Communications Glioblastoma MGMT promoter Methylation status Temozolomide Linear correlation Methylation-specific polymerase-chain-reaction |
| title | The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents |
| title_full | The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents |
| title_fullStr | The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents |
| title_full_unstemmed | The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents |
| title_short | The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents |
| title_sort | number of methylated cpg sites within the mgmt promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents |
| topic | Glioblastoma MGMT promoter Methylation status Temozolomide Linear correlation Methylation-specific polymerase-chain-reaction |
| url | https://doi.org/10.1186/s40478-021-01134-5 |
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