Comparative Analysis of CHEK1, Extrachromosomal DNA Dynamics, and 1p/19q Status in Lower-Grade and High-Grade Glioma
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Background
Extrachromosomal DNA (ecDNA) drives rapid tumor evolution, genomic instability, and therapy resistance in gliomas by amplifying oncogenes and generating intratumoral heterogeneity. These genomic alterations induce replication–transcription conflicts, creating a dependence on checkpoint kinase 1 (CHK1), encoded by CHEK1 , to resolve replication stress.
Methods
We analyzed genomic, transcriptomic, and clinical data from The Cancer Genome Atlas (TCGA) lower-grade glioma (LGG) and glioblastoma (GBM) cohorts using UCSC Xena and cBioPortal. CHEK1 expression, copy number variation, mutation burden, and fraction of genome altered were correlated with overall survival, TP53 , and ATRX status, and 1p/19q co-deletion. Kaplan–Meier survival analyses, log-rank tests, and co-occurrence analyses were performed, and correlations with genomic instability were assessed.
Results
High CHEK1 expression and amplification were significantly associated with reduced survival, particularly in 1p/19q -non-codeleted LGG (P < 0.001). CHEK1 amplification correlated with increased mutation burden and a higher fraction of genome altered, indicating a link between replication stress signaling and chromosomal instability. Co-occurrence analysis revealed strong associations between CHEK1 alterations and TP53 mutations, highlighting their cooperative role in replication stress responses. In contrast, 1p/19q -codeleted tumors exhibited lower CHEK1 expression and improved prognosis, suggesting reduced replication stress in this molecular subtype.
Conclusions
CHEK1 amplification and overexpression are hallmarks of ecDNA-driven gliomas, linking replication stress to poor clinical outcomes. CHEK1 status—particularly when integrated with 1p/19q co-deletion and genomic instability metrics—may serve as a prognostic biomarker and a predictive marker for therapeutic strategies targeting replication stress. These findings support the development of CHK1 inhibitors and combination approaches as precision treatments for genomically unstable gliomas. A subset of patients (1p/19q-non-codeleted LGG) where CHEK1 expression/amplification is present may have a prognostic and predictive marker for replication stress-targeted therapies.
