Comparative Analysis of CHEK1, Extrachromosomal DNA Dynamics and 1p/19q Status in Lower Grade and High Grade Glioma

BackgroundExtrachromosomal 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. MethodsWe 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. ResultsHigh 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. ConclusionsCHEK1 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.