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Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment

Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment re...

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Autores principales: Lozinski, Mathew, Bowden, Nikola A., Graves, Moira C., Fay, Michael, Day, Bryan W., Stringer, Brett W., Tooney, Paul A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997841/
https://www.ncbi.nlm.nih.gov/pubmed/35406779
http://dx.doi.org/10.3390/cells11071215
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author Lozinski, Mathew
Bowden, Nikola A.
Graves, Moira C.
Fay, Michael
Day, Bryan W.
Stringer, Brett W.
Tooney, Paul A.
author_facet Lozinski, Mathew
Bowden, Nikola A.
Graves, Moira C.
Fay, Michael
Day, Bryan W.
Stringer, Brett W.
Tooney, Paul A.
author_sort Lozinski, Mathew
collection PubMed
description Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition.
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spelling pubmed-89978412022-04-12 Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment Lozinski, Mathew Bowden, Nikola A. Graves, Moira C. Fay, Michael Day, Bryan W. Stringer, Brett W. Tooney, Paul A. Cells Article Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition. MDPI 2022-04-04 /pmc/articles/PMC8997841/ /pubmed/35406779 http://dx.doi.org/10.3390/cells11071215 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lozinski, Mathew
Bowden, Nikola A.
Graves, Moira C.
Fay, Michael
Day, Bryan W.
Stringer, Brett W.
Tooney, Paul A.
Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment
title Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment
title_full Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment
title_fullStr Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment
title_full_unstemmed Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment
title_short Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment
title_sort transcriptomic profiling of dna damage response in patient-derived glioblastoma cells before and after radiation and temozolomide treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997841/
https://www.ncbi.nlm.nih.gov/pubmed/35406779
http://dx.doi.org/10.3390/cells11071215
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