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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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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 |
Sumario: | 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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