TY - JOUR
T1 - Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
AU - van de Geer, Wesley S
AU - Hoogstrate, Youri
AU - Draaisma, Kaspar
AU - Robe, Pierre A
AU - Bins, Sander
AU - Mathijssen, Ron H J
AU - French, Pim
AU - van de Werken, Harmen J G
AU - de Vos, Filip Y F
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
PY - 2022/1/21
Y1 - 2022/1/21
N2 - 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.
AB - 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.
KW - genomics
KW - glioblastoma
KW - precision medicine
KW - whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85134982020&partnerID=8YFLogxK
U2 - 10.1093/noajnl/vdab177
DO - 10.1093/noajnl/vdab177
M3 - Article
C2 - 35047820
SN - 2632-2498
VL - 4
SP - 1
EP - 11
JO - Neuro-oncology advances
JF - Neuro-oncology advances
IS - 1
M1 - vdab177
ER -