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Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas

BACKGROUND: The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy, and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve p...

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Autores principales: van de Geer, Wesley S, Hoogstrate, Youri, Draaisma, Kaspar, Robe, Pierre A, Bins, Sander, Mathijssen, Ron H J, French, Pim, van de Werken, Harmen J G, de Vos, Filip Y F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760899/
https://www.ncbi.nlm.nih.gov/pubmed/35047820
http://dx.doi.org/10.1093/noajnl/vdab177
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author van de Geer, Wesley S
Hoogstrate, Youri
Draaisma, Kaspar
Robe, Pierre A
Bins, Sander
Mathijssen, Ron H J
French, Pim
van de Werken, Harmen J G
de Vos, Filip Y F
author_facet van de Geer, Wesley S
Hoogstrate, Youri
Draaisma, Kaspar
Robe, Pierre A
Bins, Sander
Mathijssen, Ron H J
French, Pim
van de Werken, Harmen J G
de Vos, Filip Y F
author_sort van de Geer, Wesley S
collection PubMed
description BACKGROUND: The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy, and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole-genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS. METHODS: Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs), and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes, and potential targeted therapies. RESULTS: Tumor mutational burden (TMB) was similar to other WGS efforts (1–342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent noncoding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples. CONCLUSIONS: With high-quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients.
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spelling pubmed-87608992022-01-18 Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas van de Geer, Wesley S Hoogstrate, Youri Draaisma, Kaspar Robe, Pierre A Bins, Sander Mathijssen, Ron H J French, Pim van de Werken, Harmen J G de Vos, Filip Y F Neurooncol Adv Basic and Translational Investigations BACKGROUND: The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy, and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole-genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS. METHODS: Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs), and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes, and potential targeted therapies. RESULTS: Tumor mutational burden (TMB) was similar to other WGS efforts (1–342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent noncoding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples. CONCLUSIONS: With high-quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients. Oxford University Press 2021-11-30 /pmc/articles/PMC8760899/ /pubmed/35047820 http://dx.doi.org/10.1093/noajnl/vdab177 Text en © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic and Translational Investigations
van de Geer, Wesley S
Hoogstrate, Youri
Draaisma, Kaspar
Robe, Pierre A
Bins, Sander
Mathijssen, Ron H J
French, Pim
van de Werken, Harmen J G
de Vos, Filip Y F
Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
title Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
title_full Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
title_fullStr Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
title_full_unstemmed Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
title_short Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
title_sort landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760899/
https://www.ncbi.nlm.nih.gov/pubmed/35047820
http://dx.doi.org/10.1093/noajnl/vdab177
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