Epco-49. myc amplification at diagnosis regulates therapy-induced hypermutation at recurrent glioma

Abstract Cancer progression and resistance to therapy are driven by clonal evolution. Recent studies have shown that adult diffuse gliomas have divergent clonal dynamics. However, the genomic and epigenomic factors that influence molecular changes after treatment are not well understood. To address this, we analyzed sequencing and clinical data from 544 adult diffuse glioma patients to identify predictors of cancer evolution. Using machine learning methods CELLO2, we predict grade progression and treatment-induced hypermutation based on tumor characteristics and clinical features collected at diagnosis. We found that MYC copy number gain is more prevalent as a founding alteration in the East Asian gliomas and it is the most significant predictor of hypermutation under temozolomide treatment. Further experiments using patient-derived gliomaspheres and established glioma cell lines confirmed the critical role of MYC amplification and pathway activation in hypermutagenesis. We also showed that c-Myc binding to open chromatin and transcriptionally active regions increases the vulnerability of genomic regions to TMZ-induced mutagenesis. This study highlights MYC as an early predictor of cancer evolution and provides a machine learning platform to improve patient management by predicting cancer dynamics.