Deep‐targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma
Menglin Xiao, Xiaoteng Cui, Can Xu, Lei Xin, Jixing Zhao, Shixue Yang, Biao Hong, Yanli Tan, Jie Zhang, Xiang Li, Jie Li, Chunsheng Kang, Chuan Fang - Pharmacology (medical)
- Physiology (medical)
- Psychiatry and Mental health
- Pharmacology
Abstract
Aims
To investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair‐related genes and the development of chemoresistance in gliomas.
Methods
We conducted a comprehensive analysis of deep‐targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I‐TASSER for homology modeling. We elucidated the functional changes induced by high‐frequency site mutations in these genes and investigated their impact on glioma progression.
Results
The analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis.
Conclusion
The ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.