MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value
Abstract Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01622-w |
| _version_ | 1797451108116856832 |
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| author | Henning Leske Ulrike Camenisch Gross Silvia Hofer Marian Christoph Neidert Sabine Leske Michael Weller Dirk Lehnick Elisabeth Jane Rushing |
| author_facet | Henning Leske Ulrike Camenisch Gross Silvia Hofer Marian Christoph Neidert Sabine Leske Michael Weller Dirk Lehnick Elisabeth Jane Rushing |
| author_sort | Henning Leske |
| collection | DOAJ |
| description | Abstract Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment. |
| first_indexed | 2024-03-09T14:50:08Z |
| format | Article |
| id | doaj.art-33e017ab7b274a908ad9c8f3bd455b8c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-09T14:50:08Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-33e017ab7b274a908ad9c8f3bd455b8c2023-11-26T14:31:48ZengBMCActa Neuropathologica Communications2051-59602023-08-0111111210.1186/s40478-023-01622-wMGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic valueHenning Leske0Ulrike Camenisch Gross1Silvia Hofer2Marian Christoph Neidert3Sabine Leske4Michael Weller5Dirk Lehnick6Elisabeth Jane Rushing7Department of Pathology, Oslo University HospitalDepartment of Pathology, University Hospital of ZurichDepartment of Neurology, University Hospital and University of ZurichDepartment of Neurosurgery, University Hospital of ZurichUniversity of Oslo (UiO)Department of Neurology, University Hospital and University of ZurichDepartment of Health Sciences and Medicine, Head Biostatistics and Methodology, University of LucerneDepartment of Neuropathology, University Hospital of ZurichAbstract Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment.https://doi.org/10.1186/s40478-023-01622-wGlioblastomaMGMTSurvivalEnhancerPrognosisTemozolomide |
| spellingShingle | Henning Leske Ulrike Camenisch Gross Silvia Hofer Marian Christoph Neidert Sabine Leske Michael Weller Dirk Lehnick Elisabeth Jane Rushing MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value Acta Neuropathologica Communications Glioblastoma MGMT Survival Enhancer Prognosis Temozolomide |
| title | MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value |
| title_full | MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value |
| title_fullStr | MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value |
| title_full_unstemmed | MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value |
| title_short | MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value |
| title_sort | mgmt methylation pattern of long term and short term survivors of glioblastoma reveals cpgs of the enhancer region to be of high prognostic value |
| topic | Glioblastoma MGMT Survival Enhancer Prognosis Temozolomide |
| url | https://doi.org/10.1186/s40478-023-01622-w |
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