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Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes

BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to methylguanin‐O6-methyltransferase promoter (MGMT) promoter hypermethylated tumors. Further resistance markers are largely unknown and would help for better strat...

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Autores principales: Kessler, Tobias, Berberich, Anne, Sadik, Ahmed, Sahm, Felix, Gorlia, Thierry, Meisner, Christoph, Hoffmann, Dirk C., Wick, Antje, Kickingereder, Philipp, Rübmann, Petra, Bendszus, Martin, Opitz, Christiane, Weller, Michael, van den Bent, Martin, Stupp, Roger, Winkler, Frank, Brandes, Alba, von Deimling, Andreas, Platten, Michael, Wick, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666733/
https://www.ncbi.nlm.nih.gov/pubmed/32991787
http://dx.doi.org/10.1002/cam4.3447
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author Kessler, Tobias
Berberich, Anne
Sadik, Ahmed
Sahm, Felix
Gorlia, Thierry
Meisner, Christoph
Hoffmann, Dirk C.
Wick, Antje
Kickingereder, Philipp
Rübmann, Petra
Bendszus, Martin
Opitz, Christiane
Weller, Michael
van den Bent, Martin
Stupp, Roger
Winkler, Frank
Brandes, Alba
von Deimling, Andreas
Platten, Michael
Wick, Wolfgang
author_facet Kessler, Tobias
Berberich, Anne
Sadik, Ahmed
Sahm, Felix
Gorlia, Thierry
Meisner, Christoph
Hoffmann, Dirk C.
Wick, Antje
Kickingereder, Philipp
Rübmann, Petra
Bendszus, Martin
Opitz, Christiane
Weller, Michael
van den Bent, Martin
Stupp, Roger
Winkler, Frank
Brandes, Alba
von Deimling, Andreas
Platten, Michael
Wick, Wolfgang
author_sort Kessler, Tobias
collection PubMed
description BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to methylguanin‐O6-methyltransferase promoter (MGMT) promoter hypermethylated tumors. Further resistance markers are largely unknown and would help for better stratification. METHODS: Clinical data and methylation profiles from the NOA‐08 (104, elderly glioblastoma) and the EORTC 26101 (297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg Neuro‐Oncology center have been analyzed focused on the predictive effect of DNA damage response (DDR) gene methylation. Candidate genes were validated in vitro. RESULTS: Twenty‐eight glioblastoma 5'‐cytosine‐phosphat‐guanine‐3' (CpGs) from 17 DDR genes negatively correlated with expression and were used together with telomerase reverse transcriptase (TERT) promoter mutations in further analysis. CpG methylation of DDR genes shows highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) II glioblastoma subgroup. MES tumors have lower tumor purity compared to RTK I and II subgroup tumors. CpG hypomethylation of DDR genes TP73 and PRPF19 correlated with worse patient survival in particular in MGMT promoter unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival. Primary glioma cells show methylation patterns that resemble RTK I and II glioblastoma and long term established glioma cell lines do not match with glioblastoma subtypes. Silencing of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide in vitro. CONCLUSION: Hypomethylation of DDR genes and TERT promoter mutations is associated with worse tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in IDH wild‐type glioblastoma.
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spelling pubmed-76667332020-11-20 Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes Kessler, Tobias Berberich, Anne Sadik, Ahmed Sahm, Felix Gorlia, Thierry Meisner, Christoph Hoffmann, Dirk C. Wick, Antje Kickingereder, Philipp Rübmann, Petra Bendszus, Martin Opitz, Christiane Weller, Michael van den Bent, Martin Stupp, Roger Winkler, Frank Brandes, Alba von Deimling, Andreas Platten, Michael Wick, Wolfgang Cancer Med Clinical Cancer Research BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to methylguanin‐O6-methyltransferase promoter (MGMT) promoter hypermethylated tumors. Further resistance markers are largely unknown and would help for better stratification. METHODS: Clinical data and methylation profiles from the NOA‐08 (104, elderly glioblastoma) and the EORTC 26101 (297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg Neuro‐Oncology center have been analyzed focused on the predictive effect of DNA damage response (DDR) gene methylation. Candidate genes were validated in vitro. RESULTS: Twenty‐eight glioblastoma 5'‐cytosine‐phosphat‐guanine‐3' (CpGs) from 17 DDR genes negatively correlated with expression and were used together with telomerase reverse transcriptase (TERT) promoter mutations in further analysis. CpG methylation of DDR genes shows highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) II glioblastoma subgroup. MES tumors have lower tumor purity compared to RTK I and II subgroup tumors. CpG hypomethylation of DDR genes TP73 and PRPF19 correlated with worse patient survival in particular in MGMT promoter unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival. Primary glioma cells show methylation patterns that resemble RTK I and II glioblastoma and long term established glioma cell lines do not match with glioblastoma subtypes. Silencing of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide in vitro. CONCLUSION: Hypomethylation of DDR genes and TERT promoter mutations is associated with worse tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in IDH wild‐type glioblastoma. John Wiley and Sons Inc. 2020-09-29 /pmc/articles/PMC7666733/ /pubmed/32991787 http://dx.doi.org/10.1002/cam4.3447 Text en © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Cancer Research
Kessler, Tobias
Berberich, Anne
Sadik, Ahmed
Sahm, Felix
Gorlia, Thierry
Meisner, Christoph
Hoffmann, Dirk C.
Wick, Antje
Kickingereder, Philipp
Rübmann, Petra
Bendszus, Martin
Opitz, Christiane
Weller, Michael
van den Bent, Martin
Stupp, Roger
Winkler, Frank
Brandes, Alba
von Deimling, Andreas
Platten, Michael
Wick, Wolfgang
Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
title Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
title_full Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
title_fullStr Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
title_full_unstemmed Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
title_short Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
title_sort methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within ddr genes
topic Clinical Cancer Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666733/
https://www.ncbi.nlm.nih.gov/pubmed/32991787
http://dx.doi.org/10.1002/cam4.3447
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