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

Wesley S. Van De Geer, Youri Hoogstrate, Kaspar Draaisma, Pierre A. Robe, Sander Bins, Ron H.J. Mathijssen, Pim French*, Harmen J.G. Van De Werken*, Filip Y.F. De Vos

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article numbervdab177
JournalNeuro-Oncology Advances
Volume4
Issue number1
Early online date30 Nov 2021
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

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