ATRX mutation modifies the DNA damage response in glioblastoma multiforme tumor cells and enhances patient prognosis.

Abstract

The presence of specific genetic mutations in patients with glioblastoma multiforme (GBM) is associated with improved survival outcomes. Disruption of the DNA damage response (DDR) pathway in tumor cells enhances the effectiveness of radiotherapy drugs, while increased mutational burden following tumor cell damage also facilitates the efficacy of immunotherapy. The ATRX gene, located on chromosome X, plays a crucial role in DDR. The aim of this research is to elucidate the correlation between ATRX mutations and GBM. Dataset obtained from TCGA-GBM were conducted an analysis on the genomic features, biological characteristics, immunopathological markers, and clinical prognosis of patients carrying ATRX mutations. Our findings revealed a significantly elevated level of microsatellite instability in individuals with ATRX mutants, along with significant alterations in the receptor-tyrosine kinase (RTK)-ras pathway among patients exhibiting combined ATRX mutations. TCGA-GBM patients with concurrent ATRX mutations exhibited sensitivity to 26 chemotherapeutic and anticancer drugs, which exerted their effects by modulating the DDR of tumor cells through highly correlated mechanisms involving the RTK-ras pathway. Additionally, we observed an enrichment of ATRX mutations in specific pathways associated with DDR among TCGA-GBM patients. Our model also demonstrated prolonged overall survival in patients carrying ATRX mutations, particularly showing strong predictive value for 3- and 5-year survival rates. Furthermore, additional protective factors such as younger age, female gender, combined IDH mutations, and TP53 mutations were identified. The results underscore the protective role and prognostic significance of ATRX mutations in GBM as a potential therapeutic target and biomarker for patient survival.